Drug depot implant designs and methods of implantation

ABSTRACT

The present invention relates to novel drug depot implant designs for optimal delivery of therapeutic agents to subjects. The invention provides a method for alleviating pain associated with neuromuscular or skeletal injury or inflammation by targeted delivery of one or more therapeutic agents to inhibit the inflammatory response which ultimately causes acute or chronic pain. Controlled and directed delivery can be provided by drug depot implants, comprising therapeutic agents, specifically designed to deliver the therapeutic agent to the desired location by facilitating their implantation, minimizing their migration from the desired tissue location, and without disrupting normal joint and soft tissue movement.

FIELD OF THE INVENTION

The present invention broadly concerns drug depot implant designs foroptimal delivery of therapeutic agents to subjects. In specificapplications of the invention the compositions include novel drug depotimplant designs for optimal delivery of anti-inflammatory agents and/orgrowth factors to inhibit or eliminate the inflammatory response thatmay result in acute or chronic pain and further tissue damage afterdisease or injury.

BACKGROUND OF THE INVENTION

Current approaches for treating pain and/or inflammation involvesystemic delivery of therapeutic agents. Anti-inflammatory agents targettumor necrosis factor alpha (TNF-α) which appears early in theinflammatory cascade following infection or injury. It is produced bymonocytes, macrophages, and T lymphocytes. TNF-α exerts its primaryeffects on monocytes, synovial macrophages, fibroblasts, chondrocytes,and endothelial cells, and stimulates proinflammatory cytokine andchemokine synthesis. It activates granulocytes, and increases MHC ClassII expression. It promotes secretion of matrix metalloproteinases(MMPs), leading to cartilage matrix degradation. Because it initiates aninflammatory cascade, and has been found to be increased in closeproximity to inflamed or injured tissue, TNF-α inhibition is a targetfor pain therapy. Pro-TNF-α is expressed on the plasma membrane, thencleaved in the extracellular domain. Trimerization is required forbiological activity. TNF-α acts through two receptors (TNFRs): Type Ireceptors (p60, p55, CD 120a) are expressed constitutively on most celltypes and Type II receptors (p80, p75, CD 120b) are inducible. PopularTNF-α inhibitors act primarily to inhibit binding of TNF-α to itsreceptors. There are currently two major classes of TNF inhibitors: 1)monoclonal antibodies to TNF-α, which prevent binding of TNF-α to itstwo cell-associated signaling receptors (p55 and p75) and 2) monomericsoluble forms of p55 or p75 TNFR dimerized by linking them to animmunoglobulin (Ig) Fc fragment. These Igs bind to TNF-α with highaffinity and prevent it from binding to its cell-associated receptor.

TNF inhibitors have therefore been developed for therapeutic use fororthopedic and neuromuscular disease or injury that can cause pain, suchas rheumatoid arthritis. Currently therapeutic agents are deliveredsystemically to treat bone and cartilage related defects related todegeneration, injury, infection, malignancy or developmentalmalformation. TNF inhibitors currently in use are generally administeredsystemically via intravenous infusion and subcutaneous injection, butthere are side effects of anti-TNF therapies associated with the higherdoses and systemic administration that are common with these therapies.A major disadvantage of these systemic drug delivery systems is that theanti-inflammatories are delivered in buffered solutions that have shorthalf-lives, thereby requiring repeated administration to a patient,which can result in adverse effects due to the system of delivery ofrelatively high doses of the drug. Unfortunately, it provides a limitedquantity of agent that must move through the tissue to the target site.This method is inadequate to serve the needs of patients. Anti-TNFtherapy is generally needed over an extended period of time, so repeatedinjections are likely to be necessary. In addition, injection site painand reactions sometimes develop with anti-TNF agents.

Recently, there have been a number of attempts to develop an acceptableimplant and methods for treating disease in a patient.

U.S. Pat. No. 6,203,813 discloses an opiate antagonist implant pelletfor subcutaneous administration to a patient. According to thedisclosure, the subcutaneous implant pellet releases the opiateantagonist in the patient to effectively inhibit the effects of a numberof additive drugs to treat drug detoxification in a patient. Thesubcutaneous implant is not substantially immobilized in the tissue of apatient but is free to move about under the skin. Another drawback tothis approach is that the delivery of the therapeutic agent isaccomplished via the general systemic circulatory system and not it'slocal effect.

U.S. Pat. No. 6,735,475 discloses small implantable stimulators with atleast two electrodes that are small enough to have the electrodeslocated adjacent to a nerve structure at least partially responsible forheadache and/or facial pain. The implant works via electricalstimulation of a specified tissue and does not include a therapeuticagent component as part of the device, let alone involve delivery of atherapeutic agent to desired tissue. U.S. Pat. No. 6,735,475 describes avariety of implants, for treating headache and/or facial pain, none ofwhich are suitable for introducing therapeutic agents to a desiredtissue of a patient.

U.S. Patent Application Publication No. 20040064193 discloses an implantcomprising collagen and or other bio-resorbable materials for deploymentin select locations for regeneration of tissue. According to thedisclosure, the implant comprises a synthetic tissue substitute materialand a method and system for deploying the implant. U.S. PatentApplication Publication No. 20040064193 describes a variety of implants,for regeneration of tissue, none of which are suitable for introducingtherapeutic agents to a desired tissue of a patient.

U.S. Patent Application Publication No. 20050074481 discloses animplantable device comprising a polyelectrolytic complex forfacilitating the healing of voids in bone, cartilage and soft tissue.According to the disclosure, the implant provides in vivo culturing oftissue cells in a diverse tissue or homogeneous lesion. U.S. PatentApplication Publication No. 20050074481 describes a variety of implants,for facilitating the healing of voids in bone, cartilage and softtissue, none of which are suitable for introducing therapeutic agents toa desired tissue of a patient.

U.S. Patent Application Publication No. 20050177118 also discloses animplantable device comprising a polyelectrolytic complex forfacilitating the healing of voids in bone, cartilage and soft tissue.According to the disclosure, the implant provides in vivo culturing oftissue cells in a diverse tissue or homogeneous lesion, or fornon-systemic delivery of one or more therapeutic agents to a patient.The implant provides an electrical component as part of the device anddoes not include a therapeutic agent component as part of the device,let alone involve delivery of a therapeutic agent to desired tissue.

U.S. Patent Application Publication No. 20050152949 discloses a methodof intra-articular drug delivery comprising: selecting an attachmentzone within the subchondral bone in a synovial joint, affixing a drugrelease device in the attachment zone, the drug release devicecomprising a base affixable in the attachment zone, a sustained releasedrug carrier and a drug, the device positioned so that the devicereleases the drug into the synovial fluid of the synovial joint, and sothat agitation of the synovial fluid facilitates elution of the drugfrom the drug release device. One drawback of these implants is thatthey are fixedly attached to the bone itself in a synovial joint.Another drawback of these implants is that many of the intended patientsalready suffer from pain and inflammation, and will be subjected to morepain upon implantation of the device into the bone and possibleformation of osteophytes.

Despite the advances recently made in the art, there is an immediateneed for improved medical devices, methods and systems for targeteddelivery of therapeutic agents, such as TNF inhibitors, for thetreatment and prevention of inflammation and pain, capable of beingdelivered for an extended period of time at, or in close proximity to, atargeted site such as the site of trauma or inflammation.

SUMMARY OF THE INVENTION

The present invention fills the foregoing need by providing a drug depotimplant comprising a physical structure to facilitate implantation andretention in a synovial joint, a disc space, a spinal canal, or a softtissue surrounding the spinal canal of a subject; and a therapeuticagent that creates a concentration gradient for targeted delivery of theagent to the synovial joint, the disc space, the spinal canal, or thesoft tissue surrounding the spinal canal, muscle, tendon, ligament, orcartilage of a subject.

One aspect of the present invention, which provides the use of depots todeliver anti-inflammatory or anabolic compounds to intervertebral discsor articulating joints, has not been previously disclosed. Anotheraspect of the present invention provides specific designs and methodsfor insertion of drug depots into discs or joint capsules with minimaltissue disruption and minimal interference with normal joint motion. Themethods, systems and reagents of the present invention prevent thedepots from migrating away from the inflamed tissue, and allow for moreuniform distribution of the drug.

One aspect of the invention provides a method for reducing pain and/orinflammation, which comprises administering to a target site in asubject in need of treatment an effective amount of a pharmaceuticalcomposition comprising one or more therapeutic agents, wherein the oneor more therapeutic agents are administered by a drug depot implant. Inone embodiment, the drug depot implant comprises a body that holds thetherapeutic agent, and an anchoring system that extends from the body toprevent migration of the body from the target site.

One aspect of the present invention provides for a solid depot, whereinthe therapeutic agent is in lyophilized form within the implant andslowly releases an effective therapeutic amount of agent into thedesired location over a prolonged period of time, such as for example,up to and including six months.

In the practice of the invention, a drug depot implant is implanted in asubject at or near a target site. Non-limiting examples of such sitesinclude an inflamed nerve, a synovial joint, or a spinal site, inparticular a spinal disc site, such as the spinal disc space, the spinalcanal or the surrounding soft tissue.

In accordance with one aspect of the present invention a drug depotimplant design provides a physical feature to facilitate implantationand retention of the implant in the desired anatomical location foroptimal clinical efficiency. In one embodiment of the invention the drugdepot design is a rod shaped implant loaded with a therapeutic agent.One embodiment of the invention provides a rod shaped implant comprisingsmall barbs that minimize migration of the implant in a patient's tissueonce implanted.

The present invention provides for methods, systems and reagents thatpermit a surgeon to deliver a drug depot implant with optimal efficiencyto a target site in a subject in need of treatment. In one embodiment ofthe invention, the implant is designed to limit “backout” or forwardmovement into critical tissues. In another embodiment of the invention,the implant is positioned in adjacent soft tissue to the spinal foramenspace of inflamed nerve roots to alleviate sciatica and/or back paincaused by such inflammation. An alternative embodiment of the inventionprovides for a rod depot implant positioned into a disc space, whereinthe implant is positioned in place by the barb. In this embodiment ofthe invention the rod depot may further comprise a built-in cap or“stop” that positions the rod in place by utilizing an adjacent tissueplane, thereby permitting the active end of the rod to protrude into anarea of inflamed tissue and elute the therapeutic agent, which may be,for example, an anti-inflammatory agent. In another embodiment of theinvention the drug depot implant is positioned in the knee joint,wherein the rod cap is positioned in place by the knee capsule andelutes the therapeutic agent, such as an anti-inflammatory agent, intothe knee joint synovial fluid. Additional embodiments of the inventionprovide for positioning the drug depot implant in the shoulder, hip,other joints or spine of a patient.

In one embodiment, a targeted delivery system of one or more therapeuticagents is conveniently a catheter. In another embodiment, the targeteddelivery system is a syringe.

In one method of the invention, the targeted delivery system comprises adrug depot implant system administered locally by insertion of acatheter at or near a target site, the catheter having a proximal endand a distal end, the distal end having an opening to deliver apharmaceutical in situ, the proximal end being fluidly connected to apharmaceutical delivery pump. For example, the proximal end of thecatheter may deliver the therapeutic agent to within 10 cm of a targetsite, more particularly, to within 5 cm of the target site.

In the employment of an implant of the invention, the therapeutic agentmay inhibit inflammation mediated by TNF-α, for example when thetherapeutic agent is a TNF-α receptor inhibitor. Suitable therapeuticagents include, but are not limited to, soluble tumor necrosis factor αreceptors, pegylated soluble tumor necrosis factor α receptors,monoclonal antibodies, polyclonal antibodies, antibody fragments, COX-2inhibitors, metalloprotease inhibitors, such as TAPI, glutamateantagonists, glial cell derived neurotrophic factors (GDNF), B2 receptorantagonists, Substance P receptor (NK1) antagonists, Downstreamregulatory element antagonistic modulator (DREAM), iNOS, inhibitors oftetrodotoxin (TTX)-resistant Na+-channel receptor subtypes PN3 and SNS2,inhibitors of interleukins, such as IL-1, IL-6, IL-8 and IL-10, TNFbinding protein, dominant-negative TNF variants, Nanobodies™, kinaseinhibitors, and combinations thereof. Other suitable therapeutic agentsinclude but are not limited to Adalimumab, Infliximab, Etanercept,Pegsunercept (PEG sTNF-R1), Onercept, Kineret®, sTNF-R1, CDP-870,CDP-571, CNI-1493, RDP58, ISIS 104838, 1>3-β-D-glucans, Lenercept,PEG-sTNFRII Fc Mutein, D2E7, Afelimomab, AMG 108,6-methoxy-2-napthylacetic acid) or betamethasone, capsaicin, civamide,TNFRc, ISIS2302 and GI 129471, integrin antagonists, alpha-4 beta-7integrin antagonists, cell adhesion inhibitors, interferon gammaantagonists, CTLA4-Ig agonists/antagonists (BMS-188667), CD40 ligandantagonists, Humanized anti-IL-6 mAb (MRA, Tocilizumab, Chugai), HMGB-1mAb (Critical Therapeutics Inc.), anti-IL2R antibodies (daclizumab,basilicimab), ABX (anti IL-8 antibodies), recombinant human IL-10, HuMaxIL-15 (anti-IL 15 antibodies) and combinations thereof. Still othertherapeutic agents include, but are not limited to, NF Kappa Binhibitors, such as glucocorticoids including clonidine; nonsteroidalanti-inflammatory drugs (NSAIDs), such as salicylates, diflunisal,indomethacin, ibuprofen, naproxen, tolmetin, ketorolac, diclofenac,ketoprofen, fenamates (mefenamic acid, meclofenamic acid), enolic acids(piroxicam, meloxicam), nabumetone, celecoxib, etodolac, nimesulide,apazone, gold, sulindac and tepoxalin; antioxidants, such asdithiocarbamate, and other compounds such as sulfasalazine[2-hydroxy-5-[-4-[C2-pyridinylamino)sulfonyl]azo]benzoic acid] andsteroids, such as fluocinolone, cortisol, cortisone, hydrocortisone,fludrocortisone, prednisone, prednisolone, methylprednisolone,triamcinolone, betamethasone, dexamethasone, beclomethasone andfluticasone.

In certain embodiments, the therapeutic agent is an osteoinductivefactor. Suitable osteoinductive factors include, but are not limited to,a bone morphogenetic protein, a growth differentiation factor orbiologically active fragment or variant thereof, a LIM mineralizationprotein or biologically active fragment or variant thereof, orcombinations thereof.

Also disclosed is that the one or more therapeutic agents within thedrug depot implant are incorporated into a sustained releasepharmaceutical composition. In one embodiment, two or more therapeuticagents are incorporated into a sustained release pharmaceuticalcomposition. For example, in one embodiment two or more therapeuticagents are separately incorporated into separate biocompatible polymers.

The invention also includes a drug depot implant for treating osteolysisand/or bone resorption comprising administering a drug depot implant toan osteolytic site in a subject in need of treatment, the drug depotimplant providing an effective amount of a pharmaceutical compositioncomprising one or more therapeutic agents, wherein administration of thepharmaceutical composition is localized and sustained.

In one embodiment, the one or more therapeutic agents includes at leastone osteoinductive factor. Examples of suitable osteoinductive factorsinclude a bone morphogenetic protein, a growth differentiation factor ora biologically active fragment thereof, a LIM mineralization protein ora biologically active fragment thereof, or combinations thereof.

In yet another embodiment, a method is provided for alleviating painassociated with bone tumors, the method comprising administering to atumor site in a subject in need of treatment a drug depot implantcomprising an effective amount of one or more therapeutic agents,wherein administration of the composition is localized and sustained. Inthis method the one or more therapeutic agents includes at least oneosteoinductive factor. Suitable examples include, but are not limitedto, a bone morphogenetic protein, a growth differentiation factor or abiologically active fragment or variant thereof, a LIM mineralizationprotein or a biologically active fragment or variant thereof, orcombinations thereof.

Also provided is a system for providing pain relief medication in amammalian subject, the system comprising a depot for providingcontrolled and directed delivery of at least one therapeutic agent to atarget site in a subject in need thereof comprising an effective amountof a composition comprising at least one therapeutic agent whichdecreases inflammation at the target site. In another embodiment, thetherapeutic agent further comprises a modified release pharmaceuticalcomposition. The system can further comprise two or more therapeuticagents. In still another embodiment, a catheter is provided rather thana depot. In this embodiment, a catheter has a proximal end and a distalend, the distal end having an opening to deliver a pharmaceutical insitu, the proximal end being fluidly connected to a pharmaceutical pump.In another embodiment, the distal end of the catheter delivers thetherapeutic agent within about 10 cm of, or closer to, the target site.In another embodiment, the catheter delivers the therapeutic agentwithin about 5 cm of, or closer to, the target site. In this system, theat least one therapeutic agent may inhibit inflammation mediated byTNF-α. Suitable examples of a therapeutic agent is a TNF-α receptorinhibitor, for example, a pegylated soluble TNF-α receptor. Othersuitable therapeutic agents are listed herein. The system may furthercomprise a therapeutically effective amount of at least oneosteoinductive factor. Suitable osteoinductive factors include, but arenot limited to, a bone morphogenetic protein, a growth differentiationfactor or a biologically active fragment or variant thereof, a LIMmineralization protein or a biologically active fragment or variantthereof, or combinations thereof. In one embodiment, the system of theinvention employs a depot comprising a modified release pharmaceuticalcarrier.

The invention also includes the use of a composition comprising one ormore therapeutic agents that decrease inflammation at a target site forthe manufacture of a pharmaceutical for reducing pain, whereinadministration of an effective amount of the composition to a targetsite in a subject in need of treatment is localized and controlled.

In one embodiment, the invention is a depot for alleviating pain andlimiting bone loss associated with osteolysis, wherein theadministration of the composition to an osteolytic site in a subject inneed of treatment is localized and controlled.

In another embodiment the invention includes the use of a compositioncomprising one or more therapeutic agents that decrease inflammation ata target site for the manufacture of a pharmaceutical for alleviatingpain associated with bone tumors, wherein administration of thecomposition to a tumor site in a subject in need of treatment islocalized and controlled.

In any of the above listed uses, the composition may be a sustainedrelease pharmaceutical composition.

Also disclosed is a method for retarding tissue necrosis and/or damage,the method comprising administering to a target site in a subject inneed of treatment an effective amount of a pharmaceutical compositioncomprising one or more therapeutic agents, wherein the one or moretherapeutic agents are administered by a depot that provides localizedand sustained release of the pharmaceutical composition. In oneembodiment, the depot is implanted in a subject at or near a targetsite, such as, but not limited to, an inflamed nerve or a spinal site,for example into a spinal disc or spinal disc space.

One aspect of the invention provides a radiographic marker on the drugdepot implant to permit a surgeon to accurately position the implantinto a tissue of a patient. Examples of such radiographic markersinclude, but are not limited to, barium, calcium phosphate, and metalbeads. Such radiographic markers will also permit the surgeon to trackmovement and degradation of the implant in the tissue over time. In thisembodiment of the invention the surgeon may accurately position theimplant in the tissue using any of the numerous diagnostic imagingprocedures known to one of ordinary skill in the art. Such diagnosticimaging procedures include, for example, X-ray imaging or fluoroscopy.

Another aspect of the present invention provides for methods, systemsand reagents comprising a drug depot implant configuration for providinga concentration gradient of the therapeutic agent to the tissue of apatient. In this aspect of the invention the preferred drug depotimplant is a rod configuration that provides an optimal, therapeuticallyeffective amount of the therapeutic agent up to 1 to 5 cm from the rod.

Another aspect of the present invention provides for drug depot implantconfigurations comprising microspheres loaded with a therapeutic agent,such as a TNF-inhibitor, for targeted delivery to a desired region of apatient. In this embodiment of the invention, targeted drug depotdelivery my be achieved by any means including for example, by injectioneither into the disc space, the spinal canal, or in the surrounding softtissues. This embodiment of the present invention delivers thetherapeutic agent closer to the inflamed tissue e.g., nerve rootscausing sciatic pain, nerve fibers growing into annular tears in discscausing backpain, or knee joints with osteoarthritis. It will beappreciated by those with skill in the art that a drug delivery devicemay be delivered by a wide variety of methods, such as by placement intoa drill site, injection by syringe and/or catheter or forceful injectionby gun.

These and other objects and advantages of the present invention will beapparent from the descriptions herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a cross-sectional view of one embodiment of a drug depotimplant.

FIG. 2 is a cross-sectional view of an alternative embodiment of a drugdepot implant.

FIG. 3 is a side view of another embodiment of a drug depot implant.

FIG. 4 shows a targeted delivery device and a drug depot implant.

FIG. 5 is a side view of another drug depot implant.

FIG. 6 shows a drug depot implant with a first embodiment radiographicmarker.

FIG. 7 shows a drug depot implant with a second embodiment radiographicmarker.

FIG. 8 is a side view of an alternative embodiment of a drug depotimplant.

FIG. 9 illustrates the drug depot implant of FIG. 9 deployed in a disk.

FIG. 10 illustrates the drug depot implant of FIG. 8 deployed in ajoint.

FIG. 11 is a side view of another drug depot implant.

FIG. 12 is a side view of an alternative drug depot implant.

FIG. 13 is a side view of yet another alternative of a drug depotimplant.

FIG. 14 shows the drug depot implant of FIG. 11 deployed in a joint.

FIG. 15 shows the drug depot implant of FIG. 12 deployed in a joint.

FIG. 16 is a side view of another drug depot implant.

FIG. 17 shows the drug depot implant of FIG. 16 and an associatedtargeted delivery system.

FIG. 18 shows the drug depot implant of FIG. 16 deployed in a disc andsurrounding soft tissue.

FIG. 19 shows the drug depot implant of FIG. 16 deployed in a joint.

FIG. 20 illustrates delivery of a therapeutic agent to a spinal canaland surrounding soft tissue utilizing microspheres.

FIG. 21 illustrates delivery of a therapeutic agent to a synovial cavityutilizing microspheres.

FIG. 22 illustrates delivery of a therapeutic agent to soft tissuesurrounding a spinal canal utilizing a gel.

FIG. 23 illustrates delivery of a therapeutic agent to soft tissuesurrounding a spinal canal utilizing a gel with dispersed microspheres.

DETAILED DESCRIPTION

For the purposes of promoting an understanding of the principles of theinvention, reference will now be made to preferred embodiments andspecific language will be used to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended, such alterations and furthermodifications of the invention, and such further applications of theprinciples of the invention as illustrated herein, being contemplated aswould normally occur to one skilled in the art to which the inventionrelates.

The present invention provides methods, systems and reagents forfacilitating implantation of a drug depot implant into a subjectcomprising implanting an implant depot loaded with a therapeutic agent.The drug depot implants of the present invention may be designed forplacement and location within or near the synovial joint, the spinaldisc space, the spinal canal or the surrounding soft tissue.

The present invention also provides methods, systems and regents fordecreasing, eliminating, or managing pain—especially pain ofneuromuscular or skeletal origin—by providing direct and controlleddelivery, i.e., targeted delivery of at least one therapeutic agent toone or more sites of inflammation and sources of pain. A therapeuticagent itself may be on a continuum of rapid acting to long acting.Generally, the therapeutic agent is a component of a pharmaceuticalcomposition which can range in a continuum of rapid release to sustainedrelease. Still further, the delivery of that pharmaceutical compositionvia the targeted delivery system of the invention can include, forexample, rapid and repeating delivery at intervals or continuousdelivery. The delivery can be “local”, “direct” and “controlled.”

A drug depot implant of the present invention comprises a physicalstructure to facilitate implantation and retention in a desired locationof a subject, such as for example, a synovial joint, a disc space, aspinal canal, or a tissue of a subject; and a therapeutic agent thatprovides a concentration gradient for targeted delivery of thetherapeutic agent to the location. The implant of the present inventionprovides an optimal drug concentration gradient of the therapeutic agentat a distance of about 1 cm to about 5 cm from the implant. The implantof the present invention may further comprise an insertion cannula fordelivery of the therapeutic agent to the subject. One aspect of thepresent invention provides a depot attached to a probe, wherein theprobe is released by a pull-back mechanism for delivery of thetherapeutic agent to the subject. The implant of the present inventionmay further comprise a barb for minimizing migration of the implant in atissue of a subject. The implant of the present invention may stillfurther comprise a cap for retaining the depot in a tissue membrane orbetween tissue planes.

An aspect of the present invention provides an injectable drug depotimplant comprising microspheres loaded with a therapeutic agent, whereinthe microspheres are injected into a synovial joint, a disc space, aspinal canal, or a soft tissue surrounding the spinal canal.

Another aspect of the present invention provides a drug depot implantcomprising a gel in viscous form and microspheres loaded with atherapeutic agent, wherein the combination of gel and microspheres arepositioned into a synovial joint, disc space, a spinal canal, or a softtissue surrounding the spinal canal of a subject. In one embodiment ofthe present invention, the gel is a sprayable or injectable adherent gelthat solidifies upon contact with tissue.

One aspect of the invention provides that the viscous gel loaded withmicrospheres also delivers the microspheres to the desired inflamedtissue location and prevents the microspheres from being removed fromthat area by the venous systemic vasculature or otherwise dispersed toowidely to get the desired therapeutic effect. In this aspect of theinvention, after a few hours or days the gel may be absorbed, therebyallowing the microspheres to begin releasing the therapeutic agent. Themicrospheres do not begin releasing the agent until they are releasedfrom the gel. So, the microspheres must be formed from something that isinsoluable or inert in the gel, but soluable or active once it comesinto contact with the targeted tissue. The gel must be something thatdissolves or disperses within the subject tissue. The purpose of the gelis as you have described. As the gel begins to dissolve withinhours-days, the microspheres are exposed to body fluids and beginreleasing their contents. Examples of gels could be gelatin, PEG, orPOE. Sp the gel could be a different material from the microspheres orthe same ie. POE. The gel and microspheres are formulated to optimizeexposure time of the micospheres and release of the therapeutic agentfrom the microspheres.

The present invention provides numerous designs for the drug depot.

One aspect of the invention provides that when depot barbs are employedthey can be oriented in one direction to facilitate implantation whilealso preventing backing out or expulsion of the depot from the desiredtissue location. In another aspect of the invention the barbs could alsobe oriented in opposite directions to prevent movement in eitherdirection once implanted.

Another aspect of the invention provides that the barbs could be fixedprotrusions or flexible protrusions that deflect out once implanted.

Another aspect of the invention provides that a joint capsule depot hasbarbs in combination with a cap such that once the depot is insertedinto the wall of the joint capsule the barb deploys and holds the depotin place via the cap and deployed barbs. In this aspect of theinvention, the barbs keep the depot from backing out and the cap keepsit from completely going into the joint space. In another aspect of theinvention the depot can be designed such that the therapeutic agent isembedded only in the portion of the depot protruding into the jointspace synovial fluid. In this aspect of the invention as the jointarticulates it facilitates the distribution of the therapeutic agentthroughout the synovial fluid. In one embodiment, after 3-6 months thedepot completely degrades and so no longer transverses the jointcapsule.

In another aspect of the invention, radiopaque marks are positioned inthe depot at opposite ends of the depot to assist in determining theposition of the depot relative to the inflamed tissue to be treated. Inthis aspect of the invention the radiopaque marker could be a sphericalshape, or a ring around the depot.

The present invention contemplates the use of rod-shaped depots in jointcapsules, in which the depots contain one or more sutures for retainingthe depot up against the inside of the joint capsule.

The present invention also provides a depot shaped as a tapered rod witha bullet shaped tip to ease insertion of the depot through the jointcapsule tissue and minimize tissue disruption. In this aspect of theinvention, the depot may contain a suture that is embedded into abiodegradable rod during manufacture of the depot. In one embodiment ofthe invention, the suture is strategically positioned within the rod tofacilitate positioning the depot adjacent to the inside of the jointcapsule.

In a further embodiment, a very small hole is made in the joint capsulewith a blunt probe, then the tapered rod is slowly pushed through thishole, slowly stretching the tissues apart to minimize tissue tearing.Once the rod is fully inserted, the hole in the joint capsule closesupon itself. The suture embedded in the rod is left transversing throughthe capsule so that it can be pulled taught and knotted up against theoutside of the joint capsule, forcing the depot up against the inside ofthe joint capsule. Having the depot up against the inside of the jointcapsule will prevent the depot from interfering with normal jointmotion.

In various embodiments, the suture can exit through the ends of the rod,in the middle, or somewhere in-between. The suture can exit through justone hole through the joint capsule or through two or more holes. In apreferred design, the suture exits the rod at two points near the endsof the rod and passes through two points in the joint capsule. Thisdesign offers the advantage of holding the depot up against the insideof the joint capsule without rotating and potentially interfering withjoint motion.

Another aspect of the present invention provides several designs thatare contemplated for use in the intervetebral disc and joint capsules,which includes bead shaped depots strung together along a suture. Inthis aspect of the invention, the beads may be a drug loadedbiodegradable polymer, and the suture may be either degradable ornon-degradable material. One embodiment of the invention provides at theleading end of the suture an optional needle or barb to retain thestrand within the disc or joint capsule.

Another aspect of the invention provides that the strand may beimplanted by inserting a cannula, which contains the strand of beads,inside the disc, joint, or soft tissue as far as desired, then deployingthe barb into the soft tissue (e.g., the annulus) and slowly retractingthe cannula, which will result in the string of beads being pulled fromthe cannula. One embodiment of the invention provides that by fixing theleading edge of the string of beads, the beads are retained at thelocation where the drug is desired inside a disc, along a nerve root, ortransverse across a joint, resulting in a more uniform distribution ofthe drug.

In one embodiment, the string of drug eluting bead depots are disposedalong the route of inflamed tissue, thereby resulting in a moreeffective distribution of the drug and greater clinical effectiveness.For example, a very small hole may be made in an intervertebral disc atthe site of a possible disc herniation or in a joint capsule with ablunt probe through which a cannula may be inserted to implant thestring of beads.

Another aspect of the present invention provides a method for deliveringa therapeutic agent to a synovial joint, disc space, a spinal canal, ora soft tissue surrounding the spinal canal of a subject, comprisinginserting within the synovial joint, the disc space, the spinal canal,or the soft tissue surrounding the spinal canal of a subject, a drugdepot implant comprising a hollow depot, the hollow depot comprising atherapeutic agent that provides a concentration gradient for targeteddelivery of the agent to the synovial joint, the disc space, the spinalcanal, or the soft tissue surrounding the spinal canal of a subject. Oneembodiment of the invention provides for an optimal drug concentrationgradient extending about 1 to about 5 cm from the implant. Anotherembodiment of the present invention provides for delivering thetherapeutic agent to the synovial joint or tissue using an insertioncannula.

Another embodiment of the present invention provides for the drug depotimplant further comprising a barb for minimizing migration of theimplant in a tissue of a subject, and further comprising a cap forretaining the depot in a tissue membrane or between tissue planes.

Another aspect of the present invention provides a method for deliveringa therapeutic agent to a synovial joint, disc space, a spinal canal, ora soft tissue surrounding the spinal canal of a subject, comprisinginserting within the synovial joint, the disc space, the spinal canal,or the soft tissue surrounding the spinal canal of a subject a drugdepot implant comprising microspheres, the microspheres comprising atherapeutic agent that provides a concentration gradient for targeteddelivery of the agent to the subject, wherein the microspheres areinjected into the synovial joint, the disc space, the spinal canal, orthe soft tissue surrounding the spinal canal.

Another aspect of the present invention provides a method for deliveringa therapeutic agent to a synovial joint, a disc space, a spinal canal,or a soft tissue surrounding the spinal canal of a subject, the methodcomprising inserting within the synovial joint, the disc space, thespinal canal, or the soft tissue surrounding the spinal canal of asubject a drug depot implant comprising a gel in viscous form andmicrospheres loaded with a therapeutic agent. The combination of gel andmicrospheres are positioned into the synovial joint, the disc space, thespinal canal, or the soft tissue surrounding the spinal canal of asubject. In one embodiment of the present invention, the gel is asprayable or injectable adherent gel that hardens upon contact withtissue.

To aid in the understanding of the invention, the following non-limitingdefinitions are provided:

The terms “comprise,” “comprising,” “include,” “including,” “have,” and“having” are used in the inclusive, open sense, meaning that additionalelements may be included. The terms “such as”, “e.g.”, and “i.e.” asused herein are non-limiting and are for illustrative purposes only.“Including” and “including but not limited to” are used interchangeably.

As used herein, the term “anabolic compound” is an art-recognized termand refers to any compound that is involved in the synthesis of morecomplex substances from simpler ones in living tissue.

As used herein, the term “drug delivery device” is an art-recognizedterm and refers to any medical device suitable for the application of adrug to a targeted organ or anatomic region. The term includes thosedevices that transport or accomplish the instillation of thecompositions towards the targeted organ or anatomic area, even if thedevice itself is not formulated to include the composition. As anexample, a needle or a catheter through which the composition isinserted into an anatomic area or into a blood vessel or other structurerelated to the anatomic area is understood to be a drug delivery device.As a further example, a stent or a shunt or a catheter that has thecomposition included in its substance or coated on its surface isunderstood to be a drug delivery device. A drug delivery device caninclude a rigid or flexible container. It may include a semi-solidcomposition that releases the drug by dissolution of the device or byleaching of drug from the device. It should also be clear that “implant”covers attaching to the joint in any way, e.g., by implanting into acavity in bone or cartilage or by suturing or otherwise adhering thedevice to the surface of bone, tendon, or cartilage.

As used herein, the term “microspheres” shall mean generally sphericalparticles 10 μm-100 μm in size. Microspheres comprise a hollow spaceencapsulated by lipids, polymers, at least one surfactant, or anycombination thereof, wherein the hollow space comprises a therapeuticagent. In different embodiments, microspheres may include microbubblesand liposomes.

As used herein, the term “osteoinduction” refers to the ability tostimulate the proliferation and differentiation of pluripotentmesenchymal stem cells (MSCs). In endochondral bone formation, stemcells differentiate into chondroblasts and chondrocytes, laying down acartilaginous ECM, which subsequently calcifies and is remodeled intolamellar bone. In intramembranous bone formation, the stem cellsdifferentiate directly into osteoblasts, which form bone through directmechanisms. Osteoinduction can be stimulated by osteogenic growthfactors, although some ECM proteins can also drive progenitor cellstoward the osteogenic phenotype.

As used herein, the term “patient,” “subject,” or “host” refers to abiological system to which a treatment can be administered. A biologicalsystem can include, for example, an individual cell, a set of cells(e.g., a cell culture), an organ, or a tissue. Additionally, the term“patient” can refer to animals, including, without limitation, humans.

As used herein, the term a “targeted delivery system” is a direct andlocal administration system to deliver therapeutic agents and includes,but is not limited to, a depot, or a system administered locally byinsertion of an implant, catheter or syringe at or near a target site.In some embodiments of the invention, the catheter or syringe isoptionally operably connected to a pharmaceutical delivery pump. It isunderstood that pumps can be internal or external as appropriate. A“depot” includes, but is not limited to, capsules, microspheres,particles, gels in viscous forms, coatings, matrices, wafers, pills orother pharmaceutical delivery compositions. A depot may comprise abiopolymer that is either biodegradable or non-degradable.

A “therapeutically effective amount” is such that when administered, theagent results in alteration of the biological activity, such as, forexample, inhibition of inflammation. The dosage administered, as singleor multiple doses, to an individual will vary depending upon a varietyof factors, including the agent's pharmacokinetic properties, the routeof administration, patient conditions and characteristics (sex, age,body weight, health, size), extent of symptoms, concurrent treatments,frequency of treatment and the effect desired. Adjustment andmanipulation of established dosage ranges are well within the ability ofthose skilled in the art, as well as in vitro and in vivo methods ofdetermining the alteration of biological activity in an individual, suchas the inhibition of TNF or IL-1. According to the invention, thetherapeutic agent is used in an amount typically ranging between about0.1 to 5000 μg/kg of body weight or about 1 to 1000 μg/kg of bodyweight. Amounts of about 10 to 500 μg/kg of body weight are preferred,and amounts of about 50 to 250 μg/kg of body weight are furtherpreferred.

The term “treating” or “treatment” of a disease refers to executing aprotocol, which may include administering one or more drugs to a patient(human or otherwise), in an effort to alleviate signs or symptoms of thedisease. Alleviation can occur prior to signs or symptoms of the diseaseappearing, as well as after their appearance. Thus, “treating” or“treatment” includes “preventing” or “prevention” of disease. Inaddition, “treating” or “treatment” does not require completealleviation of signs or symptoms, does not require a cure, andspecifically includes protocols which have only a marginal effect on thepatient.

“Localized” delivery is defined herein as non-systemic delivery whereinone or more therapeutic agents are deposited within a tissue, forexample, a nerve root of the nervous system or a region of the brain, orin close proximity (within about 10 cm, or preferably within about 5 cm,for example) thereto. “Targeted delivery system” provides delivery ofone or more therapeutic agents in a quantity of pharmaceuticalcomposition that can be deposited at the target site as needed for paineither continuously or at an intermittent rate.

As used herein, the term “therapeutic agents” refers topharmacologically active substances, such as those that are direct andlocal-acting modulators of pro-inflammatory cytokines such as TNF-α andIL-1 including but not limited to, for example, soluble tumor necrosisfactor α receptors, any pegylated soluble tumor necrosis factor αreceptor, monoclonal or polyclonal antibodies or antibody fragments orcombinations thereof. Examples of suitable therapeutic agents includereceptor antagonists, molecules that compete with the receptor forbinding to the target molecule, antisense polynucleotides, andinhibitors of transcription of the DNA encoding the target protein.Suitable examples include but are not limited to Adalimumab, Infliximab,Etanercept, Pegsunercept (PEG sTNF-R1), sTNF-R1, CDP-870, CDP-571,CNI-1493, RDP58, ISIS 104838, 1>3-β-D-glucans, Lenercept, PEG-sTNFRII FcMutein, D2E7, Afelimomab, and combinations thereof. They can decreasepain through their actions as inhibitors or agonists of the release ofpro-inflammatory molecules. For example, these substances can act byinhibiting or antagonizing expression or binding of cytokines or othermolecules that act in the early inflammatory cascade, often resulting inthe downstream release of prostaglandins and leukotrienes. Thesesubstances can also act, for example, by blocking or antagonizing thebinding of excitatory molecules to nociceptive receptors in the nervoussystem or neuromuscular system, as these receptors often trigger aninflammatory response to inflammation or injury of the nerve orsurrounding tissue through a nitric oxide-mediated mechanism. Thesetherapeutic agents include, for example, inhibitors of the action oftumor necrosis factor alpha (TNF-α). Studies have demonstrated that inchronic arthritic diseases, for example, cartilage degradation continueseven when the inflammation has been suppressed. Therapeutic agents suchas anti-TNF agents are particularly effective for joint pain, forexample, because they not only decrease the inflammation that providesthe source of pain but also slow the progression of joint destructionthat may accompany the inflammatory response. Hence, local targeteddelivery of the therapeutic agents in accordance with the invention mayreduce tissue necrosis and damage.

Inflammation can be an acute response to trauma or a chronic response tothe presence of inflammatory agents. When tissues are damaged, TNF-αattaches to cells to cause them to release other cytokines that causeinflammation. The purpose of the inflammatory cascade is to promotehealing of the damaged tissue, but once the tissue is healed theinflammatory process does not necessarily end. Left unchecked, this canlead to degradation of surrounding tissues and associated chronic pain.Thus, pain can become a disease state in itself. That is, when thispathway is activated, inflammation and pain ensue. Often a vicious andseemingly endless cycle of insult, inflammation, and pain sets in.Examples of conditions in which this cycle is present include, but arenot limited to, rheumatoid arthritis, osteoarthritis, carpal tunnelsyndrome, lower back pain, lower extremity pain, upper extremity pain,tissue pain and pain associated with injury or repair of cervical,thoracic and/or lumbar vertebrae or intervertebral discs, rotator cuff,articular joint, TMJ, tendons, ligaments and muscles.

It is understood that TNF is both affected by upstream events whichmodulate its production and, in turn, affects downstream events.Alternative approaches to treating medical conditions exploit this knownfact, and therapeutic agents are designed to specifically target TNF aswell as molecules upstream, downstream and/or a combination thereof.Such approaches include, but are not limited to modulating TNF directly,modulating kinases, inhibiting cell-signaling, manipulating secondmessenger systems, modulating kinase activation signals, modulating acluster designator on an inflammatory cell, modulating other receptorson inflammatory cells, blocking transcription or translation of TNF orother targets in pathway, modulating TNF-α post-translational effects,employing gene silencing, and modulating interleukins, for example IL-1,IL-6 and IL-8. As used herein, “modulating” ranges from initiating toshutting down, and within that range is included enhancing significantlyor slightly to inhibiting significantly or slightly. The term“inhibiting” includes a downregulation which may reduce or eliminate thetargeted function, such as the production of a protein or thetranslation of an oligonucleotide sequence. For example, a givenpatient's condition may require only inhibition of a single molecule,such as TNF, or modulating more than one molecule in a cascade ofupstream and/or downstream events in the pathway.

In certain embodiments, TNF-α inhibitors reduce chronic discogenic backand leg pain if delivered by perispinal administration.

In other embodiments, a therapeutic agent is a COX2 inhibitor.Cyclooxygenase inhibitors are a class of enzymes that are believed toregulate the synthesis of prostaglandin E2 (PGE2). PGE2 may increasediscogenic back pain by inducing radioculopathy. Inhibiting COX enzymesserves to reduce low back pain. While not intending to be bound to asingle theory, it is believed that since they are regulators of PGE2s,they reduce low back pain by decreasing PGE2 production. One suitableCOX2 inhibitor (6-methoxy-2-napthylacetic acid) has been shown tosuppress PGE2 production and local inflammation in cell culture, asdescribed by Melarange et al. (1992a), “Anti-inflammatory andgastroinstestinal effects of nabumetone or its active metabolite, 6MNA(6-methoxy-2-na[hthylacetic acid): comparison with indomethacin,” AgentsActions., Spec No: C82-3; and Melarange et al. (1992b)“Anti-inflammatory and gastrointestinal effects of nabumetone or itsactive metabolite, 6-methoxy-2-naphthylacetic acid (6MNA): Comparativestudies with indomethacin,” Dig. Dis. Sci., 37(12):1847-1852. AnotherPGE2 inhibitor includes betamethasone.

Another suitable therapeutic agent is a metalloprotease inhibitor. Forexample, TAPI is a metalloprotease inhibitor which can block cleavage ofTNF-α which, in turn, will reduce production of TNF-α.

Still other suitable therapeutic agents include: glutamate antagonists,glial cell-derived neurotropic factors (GDNF), B2 receptor antagonists,Substance P receptor (NK1) antagonists such as capsaicin and civamide,Downstream regulatory element antagonistic modulator (DREAM), iNOS,inhibitors of tetrodotoxin (TTX)-resistant Na+-channel receptor subtypesPN3 and SNS2, inhibitors of interleukins such as IL-1, IL-6 and IL-8,and anti-inflammatory cytokines such as IL-10.

In one example of an alternative approach, the therapeutic agent is aTNF binding protein. One suitable such therapeutic agent is currentlyreferred to as Onercept. Formulae including Onercept, Onercept-likeagents, and derivatives are all considered acceptable. Still othersuitable therapeutic agents include dominant-negative TNF variants. Asuitable dominant-negative TNF variant includes but is not limited toDN-TNF and including those described by Steed et al. (2003),“Inactivation of TNF signaling by rationally designed dominant-negativeTNF variants,” Science, 301(5641):1895-1898. Still more embodimentsinclude the use of a recombinant adeno-associated viral (rAAV) vectortechnology platform to deliver oligonucleotides encoding inhibitors,enhancers, potentiators, neutralizers, or other modifiers. For example,in one embodiment an (rAAV) vector technology platform is used todeliver a DNA sequence that is a potent inhibitor of tumor necrosisfactor (TNF-alpha). One suitable inhibitor is TNFR:Fc. Other therapeuticagents include antibodies, including but not limited to naturallyoccurring or synthetic, double chain, single chained, or fragmentsthereof. For example, suitable therapeutic agents include molecules thatare based on single chain antibodies called Nanobodies™ (Ablynx, GhentBelgium), which are defined as the smallest functional fragment of anaturally-occurring single domain antibody.

Alternatively, therapeutic agents that inhibit kinases and/or inhibitcell signaling are employed. Therapies that fall in this category arecapable of manipulating the second messenger systems. Kinase activationsignals multiple downstream effectors, including those involvingphosphatidylinositol 3-kinase and mitogen-activated protein kinases(MAPK), p38 MAPK, Src and protein tyrosine kinase (PTK). One exampleincludes the signaling of TNFα effects is the downstream activation ofMAPK.

Examples of kinase inhibitors are Gleevec, Herceptin, Iressa, imatinib(STI571), herbimycin A, tyrphostin 47, erbstatin, genistein,staurosporine, PD98059, SB203580, CNI-1493, VX-50/702 (Vertex/Kissei),SB203580, BIRB 796 (Boehringer Ingelheim), Glaxo P38 MAP Kinaseinhibitor, RWJ67657 (J&J), UO126, Gd, SCIO-469 (Scios), RO3201195(Roche), Semipimod (Cytokine PharmaSciences) or derivatives of the abovementioned agents. Yet another embodiment of the invention provides forthe use of therapeutic agents which block the transcription ortranslation of TNF-α or other proteins in the inflammation cascade inacute pain.

Therapeutic agents which inhibit TNF-α-post translational effects areuseful in the invention. For example, the initiation of TNF-α signalingcascade results in the enhanced production of numerous factors thatsubsequently act in a paracrine and autocrine fashion to elicit furtherproduction of TNF-α as well as other pro-inflammatory agents (IL-1,IL-6, IL-8, HMG-B1). Extracellular TNF-α modifying therapeutic agentsthat act on the signals downstream of TNF-α are useful in treatingsystemic inflammatory diseases. Some of these therapeutic agents aredesigned to block other effector molecules while others block thecellular interaction needed to further induce their production, forexample, integrins and cell adhesion molecules.

Suitable therapeutic agents include: integrin antagonists, alpha-4beta-7 integrin antagonists, cell adhesion inhibitors, interferon gammaantagonists, CTLA4-Ig agonists/antagonists (BMS-188667), CD40 ligandantagonists, Humanized anti-IL-6 mAb (MRA, Tocilizumab, Chugai), HMGB-1mAb (Critical Therapeutics Inc.), anti-IL2R antibodies (daclizumab,basilicimab), ABX (anti IL-8 antibodies), recombinant human IL-10, andHuMax IL-15 (anti-IL 15 antibodies).

Other suitable therapeutic agents include IL-1 inhibitors. Interleukin-1is a pro-inflammatory cytokine similar in action to TNF-α. For example,certain inhibitors of this protein are similar to those developed toinhibit TNF-α. One such example is Kineret® (anakinra) which is arecombinant, non-glycosylated form of the human interleukin-1 receptorantagonist (IL-1Ra). Another suitable therapeutic agent is AMG 108,which is a monoclonal antibody that blocks the action of IL-1.

As mentioned above, pain can become a disease state in itself. Oneparticular area in which this is particularly true is in the lower backand legs. For example, disk herniation is a major cause of back pain andsciatica. Sciatica, or radiculopathy, is pain that radiates down theback of the legs and is generally thought to be caused by irritation ofthe roots of the sciatic nerve. Back pain can also be caused by spinalstenosis, characterized by overgrowth of bony or soft tissue in thespinal canal with associated pressure on the adjacent nerves.Degeneration of the facet joints between the vertebrae, tumors,infections, fractures, and inflammation of surrounding soft tissues canalso cause back pain.

Forces that damage the vertebrae can injure the spinal cord throughstretching, laceration, ischemia, or compression. Cancer can metastasizeto the spine, resulting in bone destruction and spinal cord compression.Prolonged, continuous pressure on an extremity can result in a crushinjury. Prior spine surgery, accompanied by the presence of spinalhardware, makes the spine stiff and vulnerable to additional injury. Inall these situations, there is an inflammatory response to the injury.This response can become the source of significant, and often chronic,pain. It is this response that the present invention can address byproviding at least one inhibitor of an activator of the response. Theinhibitor or combination of inhibitors is provided at, or in closeproximity to, the source of inflammation, and is provided in a sustaineddosage that is readily available for delivery at regular intervals,continuously, or as needed to manage the inflammatory response. Thisdosage can be provided, for example, by means of a controlledadministration system.

Excitatory amino acids such as glutamate and aspartate have been shownto play a role in the development of pain originating from nerves. Micewith blocked glutamate receptors, for example, have been shown to have areduction in their responses to pain. Glutamate binds to two majorclasses of receptors: inotropic glutamate receptors (ligand-gated ionchannels) and metabotropic receptors (G protein-coupled receptors). Theinotropic receptors in the spinal cord include the N-methyl-D-asparticacid (NMDA) receptors, theα-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, andthe kainite receptors. In the method of the present invention, one ormore therapeutic agents can include, for example, antagonists orinhibitors of glutamate binding to NMDA receptors, AMPA receptors,and/or kainate receptors.

Interleukin-1 receptor antagonists, thalidomide (a TNF-α releaseinhibitor), thalidomide analogues (which reduce TNF-α production bymacrophages), bone morphogenetic protein (BMP) type 2 and BMP-4(inhibitors of caspase 8, a TNF-α activator), quinapril (an inhibitor ofangiotensin II, which upregulates TNF-α), interferons such as IL-11(which modulate TNF-α receptor expression), and aurin-tricarboxylic acid(which inhibits TNF-α), for example, may also be useful as therapeuticagents for reducing inflammation. It is contemplated that wheredesirable a pegylated form of the above may be used.

Examples of other therapeutic agents include NF kappa B inhibitors suchas glucocorticoids, including clonidine; antioxidants, such asdilhiocarbamate, and other compounds, such as sulfasalazine[2-hydroxy-5-[-4-[c2-pyridinylamino]sulfonyl]azo]benzoic acid].

Further examples of suitable therapeutic agents include NSAIDs, such astepoxalin, salicylates, diflunisal, indomethacin, sulindac, ibuprofen,naproxen, tolmetin, ketorolac, diclofenac, ketoprofen, fenamates(mefenamic acid, meclofenamic acid), enolic acids (piroxicam,meloxicam), nabumetone, celecoxib, etodolac, nimesulide, apazone andgold; other examples include steroids, such as cortisol, cortisone,hydrocortisone, fludrocortisone, prednisone, prednisolone,methylprednisolone, triamcinolone, betamethasone, dexamethasone,beclomethasone and fluticasone.

The invention may further provide an implant comprising a pharmaceuticalcomposition comprising one or more biopolymers and at least onetherapeutic agent. Example biopolymers include, but are not limited to,poly(alpha-hydroxy acids), poly(lactide-co-glycolide) (PLGA),polylactide (PLA), polyglycolide (PG), polyethylene glycol (PEG)conjugates of poly(alpha-hydroxy acids), polyorthoesters, polyaspirins,polyphosphagenes, collagen, starch, chitosans, gelatin, alginates,dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA,PEGT-PBT copolymer (polyactive), methacrylates,poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAAcopolymers, PLGA-PEO-PLGA, polyphosphoesters, polyanhydrides,polyester-anhydrides, polyamino acids, polyurethane-esters,polyphosphazines, polycaprolactones, polytrimethylene carbonates,polydioxanones, polyamide-esters, polyketals, polyacetals,glycosaminoglycans, hyaluronic acid, hyaluronic acid esters,polyethylene-vinyl acetates, silicones, polyurethanes, polypropylenefumarates, polydesaminotyrosine carbonates, polydesaminotyrosinearylates, polydesaminotyrosine ester carbonates, polydesamnotyrosineester arylates, polyethylene oxides, polyorthocarbonates,polycarbonates, or copolymers or physical blends thereof or combinationsthereof. The biopolymer may also provide for non-immediate (i.e.,sustained) release. Examples of suitable sustained release biopolymersinclude, but are not limited to, poly(alpha-hydroxy acids),poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PG), polyethylene glycol (PEG) conjugates of poly(alpha-hydroxy acids),polyorthoesters, polyaspirins, polyphosphagenes, collagen, starch,chitosans, gelatin, alginates, dextrans, vinylpyrrolidone, polyvinylalcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive),methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics),PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, or combinations thereof.

The present invention also comtemplates that a gel may be utilized withthe drug depot implant, provided that the gel has a consistencysufficient to hold the therapeutic agent i.e., be in a viscous form.

The therapeutic agent, such as for example BMP, may be provided infreeze-dried form and reconstituted in collagen gel, or any othersuitable gel carrier. Any suitable gel carrier capable of delivering thetherapeutic agent to the target is contemplated.

In certain embodiments, the dosage is provided by means of a drug depotimplant, implanted to provide the dosage at, or in close proximity to,the target site.

The ability to deliver pharmaceutical compositions comprisingtherapeutic agents in effective amounts directly to the site of traumaand/or inflammation is problematic in certain respects. As used herein,a pharmaceutical composition comprises at least one therapeutic agent,as part of a drug depot implant and optionally diluents, excipients andother pharmaceutically acceptable agents desirable for improvedstability, manufacturing, efficacy and the like.

It is desirable that the targeted delivery system be able to accurately,precisely and reliably deliver the intended amount of drug over theintended period of time. Many therapeutic agents are quite expensive,especially those formulated to retain stability and efficacy overextended periods of time. Thus, the ability to efficiently formulate,process, package and deliver the therapeutic agent delivered via thetargeted delivery system with minimal loss of drug stability andefficacy is desirable. It is desirable that the pharmaceuticalcompositions suitable for targeted delivery systems of the instantinvention be carefully formulated for the desired medical effect in acontrolled, local and direct manner. Among the features of the inventionis the flexibility of the dosing option made possible due to the uniquecombinations of the controlled administration system(s) and thepharmaceutical compositions. The drug itself may be on a continuum ofrapid acting to long acting. Further, the pharmaceutical compositionitself can range in a continuum of rapid release or sustained release.Still further, the options for delivery of that pharmaceuticalcomposition is on a continuum and includes but is not limited to rapidand repeating delivery at intervals ranging to continuous delivery.Delivery may occur at a desired site over a desired period of time foradequate distribution and absorption in the patient. Advantageously,when the targeted delivery system is implanted, the delivery is capableof being directed to sites which are deep, complicated, painful ordangerous to reach by conventional means and/or otherwise inaccessible.As used throughout, the term “a” is intended to include the singular aswell as plural.

In one embodiment, the invention provides localized delivery in acontrolled manner, such as that provided by the targeted delivery systemof the invention. In such an embodiment, the continued up and downcycling of therapeutic agent levels in the patient can be avoided,allowing the body to adjust more easily to the level of the therapeuticagent. Side effects can therefore be minimized.

The targeted delivery system of the invention may additionally include,for example, an infusion pump that administers a pharmaceuticalcomposition through a catheter near the spine or one or more inflamedjoints, an implantable mini-pump that can be inserted at an inflammatorysite or site of injury or surgery, an implantable controlled releasedevice (such as, for example, the device described in U.S. Pat. No.6,001,386), and a sustained release delivery system (such as the systemdescribed in U.S. Pat. No. 6,007,843).

The pharmaceutical composition can also be administered in a controlledand sustained manner by implanting the desired one or more therapeuticagents dispersed within a depot such as polymer matrix that breaks downover time within the tissues, or otherwise incorporated within aprotective coating that provides for the delay of the release of the oneor more therapeutic agents.

One example of a suitable pump is the SynchroMed® (Medtronic,Minneapolis, Minn.) pump. This pump has three sealed chambers. Onecontains an electronic module and battery. The second contains aperistaltic pump and drug reservoir. The third contains an inert gas,which provides the pressure needed to force the pharmaceuticalcomposition into the peristaltic pump. To fill the pump, thepharmaceutical composition is injected through the reservoir fill portto the expandable reservoir. The inert gas creates pressure on thereservoir, and the pressure forces the pharmaceutical compositionthrough a filter and into the pump chamber. The pharmaceuticalcomposition is then pumped out of the device from the pump chamber andinto the catheter, which will direct it for deposit at the target site.The rate of delivery of pharmaceutical composition is controlled by amicroprocessor. This allows the pump to be used to deliver similar ordifferent amounts of pharmaceutical composition continuously, atspecific times, or at set intervals between deliveries.

Potential drug delivery devices suitable for adaptation for the methodof the invention include but are not limited to those described, forexample, in U.S. Pat. No. 6,551,290 (Elsberry, et al.), which describesa medical catheter for target specific drug delivery; U.S. Pat. No.6,571,125 (Thompson), which describes an implantable medical device forcontrollably releasing a biologically-active agent; U.S. Pat. No.6,594,880 (Elsberry), which describes an intraparenchymal infusioncatheter system for delivering therapeutic agents to selected sites inan organism; and U.S. Pat. No. 5,752,930 (Rise, et al.), which describesan implantable catheter for infusing equal volumes of agents to spacedsites.

Additional designs which may be adapted to be employed in the method ofthe present invention are provided, for example, in United States PatentApplications such as US 2002/0082583 (a pre-programmable implantableapparatus with a feedback regulated delivery method), US 2004/0106914 (amicro-reservoir osmotic release system for controlled release ofchemicals), US 2004/0064088 (a small, light-weight device for deliveringliquid medication), US 2004/0082908 (an implantable microminiatureinfusion device), US 2004/0098113 (an implantable ceramic valve pumpassembly), and US 2004/0065615 (an implantable infusion pump with acollapsible fluid chamber). Alzet® osmotic pumps (Durect Corporation,Cupertino, Calif.) are also available in a variety of sizes, pumpingrates and durations suitable for use in the method of the presentinvention.

The polymers of the present invention may be employed in the preparationof extended-release or sustained release compositions for use in themethod of the present invention. In one embodiment, further excipientsare employed. The amount of excipient that is useful in the compositionof this invention is an amount that serves to uniformly distribute theactive agent throughout the composition so that it can be uniformlydispersed when it is to be delivered to a subject in need thereof. Itmay serve to dilute the therapeutic agent to a concentration at whichthe therapeutic agent can provide the desired beneficial palliative orcurative results while at the same time minimizing any adverse sideeffects that might occur from too high a concentration. It may also havea preservative effect. Thus, for a therapeutic agent that has highphysiological activity, more of the excipient will be employed. On theother hand, for a therapeutic agent that exhibits a lower physiologicalactivity a lesser quantity of the excipient will be employed. Ingeneral, the amount of excipient in the composition will be betweenabout 50% weight (w) and 99.9% w. of the total composition. Fortherapeutic agent that have a particularly high physiological activity,the amount will be between about 98.0% and about 99.9% w.

Delivery of therapeutic agents to decrease or eliminate pain in a humanor animal subject by the method and systems of the present invention canbe effective for alleviating pain, although amounts of any one or moretherapeutic agents administered to a particular subject are at least oneorder of magnitude less than those amounts of therapeutic agents, suchas TNF-α inhibitors or antagonists, that are provided to individuals whoundergo systemic infusion or injection. By providing one or moretherapeutic agents at or in close proximity to the site of inflammationor nerve damage, particularly when those therapeutic agents are providedin a controlled-release manner, the amount of therapeutic agents thatmust be administered in relation to conventional modes ofadministration, such as oral or by injection, is decreased. Thisincreases the pharmaceutical efficiency of the therapeutic agent,because it is being directed to the tissue in which its action willprovide the greatest effect, such as a nerve root or region of thebrain. While systemic delivery or delivery by intravenous injection mayprovide a sufficient level of therapeutic agent to produce the desiredresult, it also results in an increased risk of unwanted side-effects,such as risk of infection when anti-TNF-α compositions are repeatedlyadministered, thus resulting in increases in cost, inconvenience anddiscomfort to the patient.

Effective dosages for use in the method of the present invention can bedetermined by those of skill in the art, particularly when effectivesystemic dosages are known for a particular therapeutic agent. Dosagesmay typically be decreased by at least 90% of the usual systemic dose ifthe therapeutic agent is provided as in the method and systems of thepresent invention. In other embodiments, the dosage is at least 75%, atleast 80% or at least 85% of the usual systemic dose for a givencondition and patient population. Dosage is usually calculated todeliver a minimum amount of one or more therapeutic agents per day,although daily administration is not required. If more than onepharmaceutical composition is administered, the interaction between thesame is considered and the dosages calculated. Intrathecal dosage, forexample, can comprise approximately ten percent of the standard oraldosage. Alternatively, an intrathecal dosage is in the range of about10% to about 25% of the standard oral dosage.

The targeted delivery system of the invention can be positioned todeliver at the site of injury which is causing or will causeinflammation, such as a surgical site, or within about 0.5 to about 10cm, or preferably less than 5 cm, for example, of the injury orinflammatory site. This site can comprise one or multiple sites in thespine, such as between the cervical, thoracic, or lumbar vertebrae, orcan comprise one or multiple sites located within the immediate area ofinflamed or injured joints, such as the shoulder, hip, or other joints.Implantation of the drug depot implant can occur simultaneously withsurgery to repair a fracture, remove a tumor, etc., or can be performedin individuals who experience pain, especially chronic pain, as theresult of earlier trauma, injury, surgery, or other initiation ofinflammation.

In one embodiment, a targeted delivery system comprises an interbodypump and a catheter, the catheter having a proximal end and a distalend, the distal end having an opening to deliver a pharmaceuticalcomposition in situ and a proximal end of the catheter being fluidlyconnected to the interbody pump.

Timing of doses can also be determined by a physician or otherappropriate health care professional, or the patient, based upon thecondition, for example, severity and duration of pain. Duration ofadministration of therapeutic agents, interval between doses, size ofdose, continuity or spontaneity of dosage administration, are allappropriately determined by an individual's physician. In deciding thetiming of doses the health care professional has options such asadministering to a target site in a patient an effective amount of apharmaceutical composition comprising one or more therapeutic agents,wherein the one or more therapeutic agents are administered by atargeted delivery system. The administration can (1) be localized andsustained, (2) occur over a period of at least one day to about 6months, (3) be continuous or periodic. Further, the health care providerhas the choice of selecting a pharmaceutical composition having atargeted release rate. For example, a targeted release rate is fromabout 24 hours to about 62 days. The health care provider may vary thecombinations as the patient provides feedback over the treatment course.Accordingly, the health care provider has numerous options notpreviously available, especially in the treatment of pain, particularlychronic pain.

The methods, systems and reagents of the present invention may have bothhuman medical and veterinary use, being suitable for use in humanchildren and adults, as well as in other mammals. Implantablecontrolled-delivery devices or compositions containing therapeuticagents as described herein can be placed during orthopedic surgery tominimize inflammation and associated pain and to decrease the stimulusthat often results in chronic pain, which becomes a disease state initself.

In veterinary use, the targeted delivery system and method of theinvention may be useful for decreasing pain associated with orthopedicsurgery or injury, or orthopedic or neurological damage associated withinfection or inflammation. The method may be especially beneficial forlarger animals such as horses, or smaller domestic pets such as cats anddogs.

For human medical use, the controlled administration system and methodof the invention can be used to alleviate pain associated with rotatorcuff injury or repair, articular joint pain or repair, temporomandibularjoint disorder, tendonitis, rheumatoid and osteoarthritis, carpal tunnelsyndrome, ligament pain or repair, or targeted muscular pain relief, forexample. Examples of clinical indications for which the invention isappropriate include acute and chronic back and leg pain, whatever theorigin. In one embodiment, the therapeutic agent is delivered in thevicinity of an irritated nerve root at dose lower than current drugdosages. The therapeutic agent could be delivered over a period of a fewdays to several months, depending upon the clinical indication. Thisdirected and controlled delivery is beneficial, as certain drugs, forexample TNF-inhibitors, act to reduce the infection fighting capabilityof the immune system and therefore can lead to infection and otheradverse events. Minimizing the amount of drug (in this case therapeuticagent) and targeting a site of delivery is a significant improvementover what is currently available. Further, the versatility of thetreatment options, for example, modifying the dose and delivery at will,is unique. The health care provider can be more responsive to thepatient feedback or changing clinical manifestations. Other inflammatorydiseases may also be treated employing the invention. Therapeutic agentscan be delivered singly, in combination, in series, or simultaneously.One or multiple disc levels may be treated at the same time, withcervical, thoracic, lumbar, or multiple areas being targeted.Therapeutic agents may be applied interdiscally, adjacent to the disc,or intramuscularly. Therapeutic agents may be directed to inhibit theeffects of TNF-α, cyclooxygenase 2, prostaglandin E2, mediators ofinflammation such as glutamate, kinins such as bradykinin, and substanceP, for example, as previously described.

The invention is useful in the prevention and treatment of osteoporosis,osteoarthritis and rheumatoid arthritis. For example, rheumatoidarthritis, particularly, is known to have an inflammatory origin, andtherapeutic agents such as inhibitors of the action of TNF-α can beuseful, particularly when delivered by the implant and method of thepresent invention, for alleviating pain associated with theseconditions.

Periprosthetic osteolysis is a major complication following total jointreplacement. Articulating prosthetic joint surfaces andpolymethylmethacrylate (PMMA) cement may generate wear particles thatcause a chronic inflammatory response and osteoclastic bone resorption(wear debris-induced osteolysis), resulting in mechanical failure of theimplant. TNF and IL-1 have been shown to mediate wear debris-induced, orwear particle-induced, osteolysis. Controlled and directed delivery ofTNF inhibitors according to the controlled administration system andmethod of the present invention at an implant site provides a method forpreventing implant-associated osteolysis. Osteolysis generally, whetherwear-induced or caused by other factors, because it often occurs atindividual sites such as sites of joint replacement surgery, is anappropriate target for therapy using the controlled administrationsystems and methods of the invention. Furthermore, because TNF-α hasbeen found to induce osteoclast-like cells and the osteoclast is thecell that resorbs bone, sustained and directed (localized)administration of TNF-α inhibitors, particularly if combined withadministration of osteoinductive factors such as BMP, GDF, LMP, or acombination of both, for example, can provide both pain relief andinhibition of bone resorption.

Similarly, malignant or benign tumors of bone are often associated withbone resorption. Where tumors are removed, partially removed, or where atumor remains, there can be considerable pain. The method and system ofthe invention provides a means for alleviating such pain and making acancer patient more comfortable, as well as inhibiting bone resorptionor stimulating bone growth at the site.

In one embodiment, the method of the invention can be provided by atargeted delivery system comprising an interbody or similarpharmaceutical pump, an optional catheter fluidly connected to the pumpto provide a channel for at least one pharmaceutical composition to betransported from the pump to a target site, and a therapeutic quantityof at least one therapeutic agent such as, for example, a TNF inhibitor.In one embodiment, such a system may also comprise at least one modifiedrelease pharmaceutical carrier for the at least one therapeutic agent.

In an alternate embodiment, a depot can comprise at least one modifiedrelease pharmaceutical carrier for at least one therapeutic agent, and atherapeutically effective amount of at least one therapeutic agent, suchas, for example, a TNF inhibitor. Targeted delivery systems can beprovided as kits, comprising at least one depot provided in sterilepackaging and at least one aliquot of at least one therapeutic agent ina package so that the therapeutic agent is provided in sterile form whenintroduced into the body. Such kits can also comprise at least onepackage containing at least one aliquot of at least one therapeuticagent in combination with one or more modified release pharmaceuticalcarriers. Kits can also provide modified release carriers containing atherapeutic agent within them, the modified release carriers beingenclosed or partially enclosed within a matrix or containment device forcomplete or partial containment of the modified release carriers, thematrix or containment device being provided in sterile packaging andbeing appropriate for implantation into a target site within the body ofa subject in need of therapy utilizing the at least one therapeuticagent.

A therapeutically effective amount of an anti-inflammatory agent isadministered to a patient in need of said treatment. Theanti-inflammatory agent is selected from the group consisting of TNF,IL-1, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, GM-CSF, M-CSF, MCP-1,MIP-1, RANTES, ENA-78, OSM, FGF, PDGF, and VEGF. A variety ofanti-inflammatory agents contemplated for use in the present inventionare described in United States Patent Application Publication20030176332, which is incorporated herein by reference.

For the purposes herein, “tumor necrosis factor alpha (TNF-α)” refers toa human TNF-α molecule comprising the amino acid sequence as describedin Pennica et al., Nature, 312:721 (1984) or Aggarwal et al., JBC,260:2345 (1985). The term “human TNF-α” (abbreviated herein as hTNFα, orsimply hTNF), as used herein, also is intended to refer to a humancytokine that exists as a 17 kD secreted form and a 26 kD membraneassociated form, the biologically active form of which is composed of atrimer of noncovalently bound 17 kD molecules. The structure of hTNFα isdescribed further in, for example, Pennica, D., et al. (1984) Nature312:724-729; Davis, J. M., et al. (1987) Biochemistry 26:1322-1326; andJones, E. Y., et al. (1989) Nature 338:225-228. The term human hTNFα isintended to include recombinant human rhTNFα, which can be prepared bystandard recombinant expression methods or purchased commercially (R & DSystems, Catalog No. 210-TA, Minneapolis, Minn.). hTNFα is also referredto as TNF.

The term “TNF-α inhibitor” includes agents which interfere with abiological function of TNF-α, generally through binding-to TNF-α andneutralizing its activity. Examples of TNF-α inhibitors includeetanercept (Enbrel®, Amgen), infliximab (Remicade®, Johnson andJohnson), human anti-TNF monoclonal antibody Adalimumab (D2E7/HUMIRA®,Abbott Laboratories), CDP 571 (Celltech), and CDP 870 (Celltech), aswell as other compounds which inhibit TNF-α activity, such that whenadministered to a subject suffering from or at risk of suffering from adisorder in which TNF-α activity is detrimental, the disorder istreated. The term also includes each of the anti-TNF-α human antibodiesand antibody portions described in U.S. Pat. Nos. 6,090,382; 6,258,562;6,509,015, and in U.S. patent application Ser. Nos. 09/801,185 and10/302,356, each incorporated by reference herein.

In some embodiments, the osteoinductive compositions or factors used inthis invention as therapeutic agents further comprise a therapeuticallyeffective amount to stimulate or induce bone growth of a substantiallypure bone inductive or growth factor or protein in a pharmaceuticallyacceptable carrier. The preferred osteoinductive factors are therecombinant human bone morphogenetic proteins (rhBMPs), because they areavailable in relatively unlimited supply and do not transmit infectiousdiseases. Most preferably, the bone morphogenetic protein is a rhBMP-2,rhBMP-7 or heterodimers thereof. However, any bone morphogenetic proteinis contemplated, including bone morphogenetic proteins designated asBMP-1 through BMP-13. BMPs are available from Genetics Institute, Inc.,Cambridge, Mass. and may also be prepared by one skilled in the art, asdescribed in U.S. Pat. No. 5,187,076 to Wozney et al.; U.S. Pat. No.5,366,875 to Wozney et al.; U.S. Pat. No. 4,877,864 to Wang et al.; U.S.Pat. No. 5,108,922 to Wang et al.; U.S. Pat. No. 5,116,738 to Wang etal.; U.S. Pat. No. 5,013,649 to Wang et al.; U.S. Pat. No. 5,106,748 toWozney et al.; and PCT Patent Nos. WO93/00432 to Wozney et al.;WO94/26893 to Celeste et al.; and WO94/26892 to Celeste et al.Osteoinductive factors included within the scope of the presentinvention are BMP-1, BMP-2, rhBMP-2, BMP-3, BMP-4, rhBMP-4, BMP-5,BMP-6, rhBMP-6, BMP-7[OP-1], rhBMP-7, BMP-8, BMP-9, BMP-10, BMP-11,BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, BMP-18, Growth andDifferentiation Factors, GDF-5, Cartilage Derived Morphogenic Proteins,LIM mineralization protein, platelet derived growth factor (PDGF),transforming growth factor β (TGF-β), insulin-related growth factor-I(IGF-I), insulin-related growth factor-II (IGF-II), fibroblast growthfactor (FGF), beta-2-microglobulin (BDGF II), and rhGDF-5. Allosteoinductive factors are contemplated whether obtained as above orisolated from bone. Methods for isolating bone morphogenetic proteinfrom bone are described in U.S. Pat. No. 4,294,753 to Urist and Urist etal., 81 PNAS 371, 1984.

Recombinant BMP-2 can be used at a concentration of about 0.4 mg/ml toabout 2.5 mg/ml, preferably near 1.5 mg/ml. However, any bonemorphogenetic protein is contemplated, including bone morphogeneticproteins designated as BMP-1 through BMP-18.

The bone growth inductive factor may be supplied as a therapeutic agentfor a drug depot implant of the present invention in any suitablemanner. The osteogenic factor, preferably BMP, may be provided infreeze-dried form or in any other suitable liquid or gel carrier. Anysuitable medium or carrier capable of delivering the proteins to theimplant is contemplated. Preferably, the medium is supplemented with abuffer solution, as is known in the art.

The term “synovial joint” refers to a moveable articulation of two ormore bones. The articulation is defined by a synovial cavity, whichcontains a volume of synovial fluid, is lined with a synovial membrane,and is surrounded by a fibrous capsule. The opposing bone surfaces areeach covered with a layer of cartilage. The cartilage and synovial fluidreduce friction between the articulating bone surfaces and enable smoothmovements. Synovial joints can be further distinguished by their shape,which controls the movements they allow. For example, hinge joints actlike the hinge on a door, allowing flexion and extension in just oneplane. An example is the elbow between the humerus and the ulna. Balland socket joints, such as the hip, allow movement in several planessimultaneously. Condyloid (or ellipsoid) joints, such as the knee,permit motion in more than one plane in some positions but not others.For example, no rotation is possible in the extended knee, but somerotation is possible when the knee is flexed. Pivot joints, such as theelbow (between the radius and the ulna), allow one bone to rotate aroundanother. Saddle joints, such as at the thumb (between the metacarpal andcarpal) are so named because of their saddle shape, and allow movementin a variety of directions. Finally, gliding joints, such as in thecarpals of the wrist, allow a wide variety of movement, but not muchdistance.

Synovial joints include, but are not limited to, shoulder (glenohumeraland acromioclavicular), elbow (ulno-humeral, radio-capitellar andproximal radioulnar), forearm (radioulnar, radiocarpal, ulnocarpal),wrist (distal radioulnar, radio-carpal, ulno-carpal, mid carpal), hand(carpo-metacarpal, metocarpophalangeal, interphalangeal), spine(intervertebral), hip, knee, ankle (tibiotalar, tibiofibular), and foot(talocalcaneal, talonavicular, intertarsal, tarso-metatarsal,metatarsal-phalangeal, interphalangeal).

In some embodiments, for example, implants may be formed fromhydrophilic materials, such as hydrogels, or may be formed frombiocompatible elastomeric materials known in the art, includingsilicone, polyurethane, polyolefins such as polyisobutylene andpolyisoprene, copolymers of silicone and polyurethane, neoprene,nitrile, vulcanized rubber and combinations thereof. In a preferredembodiment, the vulcanized rubber is produced by a vulcanization processutilizing a copolymer produced, for example, as in U.S. Pat. No.5,245,098 to Summers et al., from 1-hexene and 5-methyl-1,4-hexadiene.Preferred hydrophilic materials are hydrogels. Suitable hydrogelsinclude natural hydrogels, and those formed from polyvinyl alcohol,acrylamides such as polyacrylic acid and poly (acrylonitrile-acrylicacid), polyurethanes, polyethylene glycol, poly(N-vinyl-2-pyrrolidone),acrylates such as poly(2-hydroxy ethyl methacrylate) and copolymers ofacrylates with N-vinyl pyrolidone, N-vinyl lactams, acrylamide,polyurethanes and polyacrylonitrile or may be formed from other similarmaterials that form a hydrogel. The hydrogel materials may further becross-linked to provide further strength to the implant. Examples ofdifferent types of polyurethanes include thermoplastic or thermosetpolyurethanes, aliphatic or aromatic polyurethanes, polyetherurethane,polycarbonate-urethane and silicone polyether-urethane. Other suitablehydrophilic polymers include naturally-occurring materials such asglucomannan gel, hyaluronic acid, polysaccharides, such as cross-linkedcarboxyl-containing polysaccharides, and combinations thereof.

The implants of the invention may be made of at least in part of abiocompatible material. Furthermore, in some embodiments, the implantsmay be made of an implantable material, such as a material suitable forimplantation in bone, implantation in cartilage, and/or implantation inother biomaterials in a joint. In particular, the implant may be formedat least in part of a material that can maintain its integrity duringimplantation. This may help prevent leakage of a drug in the carrierthrough a crack or fissure in the implant. In some embodiments, theimplant reservoir may be constructed from a metal, such as titanium,nickel titanium, stainless steel, anodized aluminum, or tantalum, or aplastic, such as polyethylene, nylon, or polyurethane. The implant mayalso include a material or modified material to allow for osseousintegration of the implant—i.e., bone ingrowth. Other suitable materialswill be apparent to one of ordinary skill in the art. Moreover,combinations of materials may be used.

The implants of the invention may be provided with surface featuresdefined in their outer surfaces. For example, a projection may be formedon the end walls instead of a slot. Such a projection may form astraight, flat-sided shape, an elliptical eminence, a bi-concaveeminence, a square eminence, or any other protruding shape whichprovides sufficient end-cap or tool engaging end strength and drivepurchase to allow transmission of insertional torque without breaking orotherwise damaging the eminence. Yet other surface features can bedefined on the implant. As mentioned above, the outer surface of theimplant may define barbs or other surface features that may stabilizethe drug depot implant interface with tissue and reduce micromotion.

The drug depot implants of the present invention may be designed forplacement and location within or near the synovial joint, spinal discspace, spinal canal or the surrounding soft tissue. In some embodiments,the contemplated placement and location areas of the drug depot implantswithin the desired location of the subject will not cause damage to thebone, cartilage surface or tissue, as it may be placed and secured usingan anchoring device.

In some embodiments, placement of the device in a patient may be anintra-articular region of a synovial joint where there is no interfacingarticular cartilage. It may be located, for example, within the insideof the knee capsule that is non-load-bearing and removed from thearticulation surface of the synovial joint. The device may be attachedwithin the synovial joint, allowing for continuous exposure to synovialfluid flow and resulting release of anti-inflammatory or osteogenictherapeutic agents, without damaging the articular surface that is inapposition during range of motion of the given joint.

According to another embodiment of the present invention, thetherapeutic agent, e.g., anti-inflammatory agent or osteoinductivefactor, can be packaged into gas-filled lipid-containing microspheres.The gas-filled lipid-containing microspheres may further comprisebiocompatible polymers on their outer surfaces. The present inventionprovides that the therapeutic agent may also be contained in a freezedried state within the microsphere to preserve it's stability andactivity over an extended period of time. Similarly, the presentinvention also provides that the therapeutic agent may be contained in afreeze dried state within the depots to preserve it's stability andactivity over an extended period of time.

Non-limiting examples of suitable gases are air, nitrogen, carbondioxide, oxygen, argon, fluorine, xenon, neon, helium, or any and allcombinations thereof. Furthermore, various fluorinated gaseouscompounds, such as various perfluorocarbon, hydrofluorocarbon, andsulfur hexafluoride gases may be utilized in the preparation of the gasfilled microspheres.

For the biocompatible lipid materials, it is preferred that such lipidmaterials be what is often referred to as “amphiphilic” in nature (i.e.,polar lipid), by which is meant any composition of matter which has, onthe one hand, lipophilic, i.e., hydrophobic properties, while on theother hand, and at the same time, having hydrophilic properties. Thelipid may alternatively be in the form of a monolayer, and the monolayerlipids may be used to form a single monolayer (unilamellar) arrangement.Alternatively, the monolayer lipid may be used to form a series ofconcentric monolayers, i.e., oligolamellar or multilamellar, and sucharrangements are also considered to be within the scope of theinvention.

Non-limiting examples of suitable lipids are fatty acids, lysolipids,phosphatidylcholine with both saturated and unsaturated lipids,dimyristoylphosphatidylcholine, dipentadecanoylphosphatidylcholine,dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC),distearoylphosphatidylcholine (DSPC), phosphatidylethanolamines,phosphatidylserine, phosphatidylglycerol, phosphatidylinositol,sphingolipidsglycolipids, glucolipids, sulfatides, glycosphingolipids,phosphatidic acids, palmitic acid, stearic acid, arachidonic acid, oleicacid, lipids bearing polymers, lipids bearing sulfonated mono-, di-,oligo- or polysaccharides, cholesterol, cholesterol sulfate andcholesterol hemisuccinate, tocopherol hemisuccinate, lipids with etherand ester-linked fatty acids, polymerized lipids, diacetyl phosphate,dicetyl phosphate, stearylamine, cardiolipin, phospholipids with shortchain fatty acids of 6-8 carbons in length, synthetic phospholipids withasymmetric acyl chains (e.g., with one acyl chain of 6 carbons andanother acyl chain of 12 carbons), ceramides, non-ionic liposomes,polyoxyethylene fatty alcohols, polyoxyethylene fatty alcohol ethers,polyoxyethylated sorbitan fatty acid esters, glycerol polyethyleneglycol oxystearate, glycerol polyethylene glycol ricinoleate,ethoxylated soybean sterols, ethoxylated castor oil,polyoxyethylene-polyoxypropylene polymers, and polyoxyethylene fattyacid stearates; sterol aliphatic acid esters including cholesterolsulfate, cholesterol butyrate, cholesterol iso-butyrate, cholesterolpalmitate, cholesterol stearate, lanosterol acetate, ergosterolpalmitate, and phytosterol n-butyrate; sterol esters of sugar acids,esters of sugar acids and alcohols, esters of sugars and aliphaticacids, saponins, glycerol dilaurate, glycerol trilaurate, glyceroldipalmitate, glycerol and glycerol esters, longchain alcohols,digalactosyldiglyceride,6-(5-cholesten-3.beta.-yloxy)hexyl-6-amino-6-deoxy-1-thio-.beta.-D-galactopyranoside,6-(5-cholesten-3.beta.-yloxy)hexyl-6-amino-6-deoxyl-1-thio-.alpha.-D-mannopyranoside,12-(((7′-diethylaminocoumarin-3-yl)carbonyl)methylamino)-octadecanoicacid, N->12-(((7′-diethylaminocoumarin-3-yl)carbonyl)methyl-amino)octadecanoyl!-2-aminopalmitic acid,cholesteryl)4′-trimethylammonio)butanoate,N-succinyldioleoylphosphatidylethanolamine,1,3-dipalmitoyl-2-succinylglycerol, and/or combinations thereof.

Polymers suitable for this embodiment of the present invention can benatural, semi-synthetic or synthetic. Exemplary natural polymerssuitable for use in the present invention include naturally occurringpolysaccharides, such as for example, arabinans, fructans, fucans,galactans, galacturonans, glucans, mannans, xylans (such as, forexample, inulin), levan, fucoidan, carrageenan, galatocarolose, pecticacid, pectin, amylose, pullulan, glycogen, amylopectin, cellulose,dextran, pustulan, chitin, agarose, keratan, chondroitan, dermatan,hyaluronic acid, alginic acid, xanthan gum, starch and various othernatural homopolymer or heteropolymers such as those containing one ormore of the following aldoses, ketoses, acids or amines: erythrose,threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose,mannose, gulose, idose, galactose, talose, erythrulose, ribulose,xylulose, psicose, fructose, sorbose, tagatose, mannitol, sorbitol,lactose, sucrose, trehalose, maltose, cellobiose, glycine, serine,threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid,glutamic acid, lysine, arginine, histidine, glucuronic acid, gluconicacid, glucaric acid, galacturonic acid, mannuronic acid, glucosamine,galactosamine, and neuraminic acid, and naturally occurring derivativesthereof. Exemplary semi-synthetic polymers includecarboxymethylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, methylcellulose, and methoxycellulose.Exemplary synthetic polymers suitable for use in the present inventioninclude polyethylenes (such as, for example, polyethylene glycol,polyoxyethylene, and polyethylene terephthlate), polypropylenes (suchas, for example, polypropylene glycol), polyurethanes (such as, forexample, polyvinyl alcohol (PVA), polyvinylchloride andpolyvinylpyrrolidone), polyamides including nylon, polystyrene,polylactic acids, fluorinated hydrocarbons, fluorinated carbons (suchas, for example, polytetrafluoroethylene), and polymethylmethacrylate,and derivatives thereof.

The gas-filled lipid containing microspheres of the present embodimentcan be prepared, for example, by shaking an aqueous solution comprisinga lipid in the presence of a gas at a temperature below the gel state toliquid crystalline state phase transition temperature of the lipid. Theshaking must be of sufficient force to result in the formation ofmicrospheres, particularity stabilized microspheres. The shaking may beby swirling, such as by vortexing, side-to-side, or up-and-down motion.Different types of motion may be combined. Also, the shaking may occurby shaking the container holding the aqueous lipid solution, or byshaking the aqueous solution within the container without shaking thecontainer itself. It is preferred that the motion be reciprocating inthe form of an arc between about 2 degrees and about 20 degrees, morepreferably, around 6.5 degrees. It is contemplated that both the arc andthe rate of reciprocation are critical to determining the amount andsize of the gas and gaseous precursor filled microspheres formed. It isa preferred embodiment of the present invention that the number ofreciprocations, i.e., full cycle oscillations, be within the range ofabout 1000 and about 20,000 per minute.

It would be apparent to a person skilled in the art that othertechniques of making the gas-filled lipid-containing microspheres of thepresent embodiment are available. One can create such microspheres byusing freeze-thaw, as well as techniques such as sonication, chelatedialysis, homogenization, solvent infusion, microemulsification,spontaneous formation, solvent vaporization, French pressure celltechnique, controlled detergent dialysis, and other known techniques.

The gas and gaseous precursor filled microspheres made by the methoddescribed above can then be sized by optical microscopy. It should bedetermined that the largest size of the microspheres ranges from about50 to about 60 μm and the smallest size detected should be about 8 μm.The average size should range from about 15 to 20 μm. The gas andgaseous precursor filled microspheres may then be filtered through an 8,10 or 12 μm “NUCLEPORE” membrane using a Swin-Lok Filter Holder,(Nuclepore Filtration Products, Costar Corp., Cambridge, Mass.) and a 20cc syringe (Becton Dickinson & Co., Rutherford, N.J.). The membrane maybe a 10 or 12 μm “NUCLEPORE” membrane (Nuclepore Filtration Products,Costar Corp., Cambridge, Mass.). The 10.0 μm filter is placed in theSwin-Lok Filter Holder and the cap tightened down securely. Thelipid-based microsphere solution is shaken up and it is transferred tothe 20 cc syringe via an 18 gauge needle. Approximately 12 ml of gasfilled foam solution may be placed in the syringe, and the syringescrewed onto the Swin-Lok Filter Holder. The syringe and the filterholder assembly are inverted so that the larger of the gas and gaseousprecursor filled microspheres can rise to the top. Then, the syringe isgently pushed up and the gas and gaseous precursor filled microspheresare filtered in this manner.

The survival rate (the amount of the gas and gaseous precursor filledmicrospheres that are retained after the extrusion process) of the gasand gaseous precursor filled microspheres after the extrusion throughthe 10.0 μm filter is about 83-92%. Before hand extrusion, the volume offoam is about 12 ml and the volume of aqueous solution is about 4 ml.After hand extrusion, the volume of foam is about 10-11 ml and thevolume of aqueous solution is about 4 ml.

The optical microscope may be used again to determine the sizedistribution of the extruded gas and gaseous precursor filledmicrospheres. It is determined that the largest size of the microspheresranges from about 25 to about 30 μm and the smallest size detected isabout 5 μm. The average size ranges from about 8 to about 15 μm.

Specific embodiments according to the methods of the present inventionwill now be described in the following non-limiting examples. Althoughthe invention herein has been described with reference to particularembodiments, it is to be understood that these embodiments are merelyillustrative of the principles and applications of the presentinvention. It is therefore to be understood that numerous modificationsmay be made to the illustrative embodiments and that other arrangementsmay be devised without departing from the spirit and scope of thepresent invention as defined by the following claims.

In one specific application, the present invention contemplates drugdepot implants as depicted in FIG. 1. FIG. 1 is a cross-sectional viewof a rod-shaped drug depot implant 10 comprising one or more small barbs12 that serve as anchoring devices to minimize migration of the implantin a patient's tissue once implanted. In the following, the term“rod-shaped” is intended to indicate any shape with a longitudinalaxis—i.e., is longer along one direction than in other directions; thecross-sectional shape across the longitudinal axis may be any shape, butis preferably elliptical or circular. The implant 10 comprises arod-shaped (or bullet-shaped) body 14, which is made from abiodegradable material. The non-biodegradable body could be a poroushollow chamber filled with the therapeutic agent alone or incorporatedinto a degradable polymer. It may be desireable to make itnon-degradabel to be able to retrieve it after has released it'scontents. Or the non-biodegradable body could be a small pump thatpushed the contents out pores, port(s), or a cannula. Non-limitingexamples of suitable biodegradable materials for the body 14 includepolyorthoesters (POE), polylacticglycolic acid (PLGA) polysacharides(Saber technology), polycapralactone, polyfumarate, tyrosinepolycarbonate, etc. The body 14 is solid, and a therapeutic agent 16 isdispersed throughout the material that forms the body 14. The dispersalof the therapeutic agent 16 may be even throughout the body 14.Alternatively, the concentration of the therapeutic agent 16 may vary asa function of the distance from the longitudinal centerline 18 of thebody 14, or as a function of a distance along the longitudinalcenterline 18. As the biodegradable material of the body 14 degradeswithin the tissue, the therapeutic agent 16 is released. Suitablesustained release materials may be used for the body 14 to carry the oneor more therapeutic agents 16 and control the release of the therapeuticagent(s) 16. For example, microspheres may be used to encapsulate thetherapeutic agent; the therapeutic agent-containing microspheres arethen dispersed through the body 14. The one or more barbs 12 serve as ananchoring system, and are designed to permit forward translationalmovement of the body 14 along the longitudinal axis 18, while retardingbackward translational movement. Specifically, the barbs 12 extend fromthe body 14 and point backwards along the longitudinal axis 18. Thebarbs 12 may be made from the same material from which the body 14 ismade, or from a different material. For example, the barbs 12 may bemade from a secondary material that degrades more slowly than theprimary material of the body 14, and attach to a core of such secondarymaterial that runs through the longitudinal centerline 18 of the body14. The present invention provides other designs for gradient variationsin biodegradabilitiy to hold the depot in place while the secondarymaterial releases it's contents. The barbs could be a “snap-on”component that fits over the depot containing the therapeutic agent. Inthis embodiment the manufacturing of the drug loaded depot is madeeasier instead of having to injection mold the barbs into the depot. Thebarbs 12 may be axially aligned or circumferentially spaced in relationto each other about the drug depot implant 10. In certain embodiments,the implant 10 may be designed to be affixable within a joint. Theimplant 10 may have a width from about 1 mm to about 6 mm, and a lengthfrom about 5 mm to about 20 mm. Selection of suitable lengths and widthsfor the device 10 will depend upon the targeted implant site, and iswell within the abilities of those having ordinary skill in the art.

FIG. 2 is a cross-sectional view of another implant 20. As with theprevious example, the implant 20 comprises one or more barbs 22 thatpermit forward motion of the implant 20, while retarding backwardmotion, thus serving as an anchoring system to anchor the implant 20within the targeted delivery site. The implant 20 comprises a rod-shapedshell 24 that is made from a non-biodegradable material, such aspolyethylene, delrin, polyurethane. Alternatively, the shell 24 may bemade from a bio-degradable material that degrades relatively slowlywithin the implant site; suitable materials include [POE, PLGA, PLA,PGA, all the other standard degradable polymers. The shell 24 forms acavity 25, and one or more therapeutic agents 26 are disposed within thecavity 25. The therapeutic agents 26 may be, for example, infreeze-dried form, dispersed in a carrier, contained withinmicrospheres, or packed in any other suitable manner within the cavity25. The shell 24 is permeable to the therapeutic agent 26, howeverpacked, so that the therapeutic agent 26 can diffuse through the shell24 and into the surrounding tissue. For example, in the case where theshell 24 holds therapeutic agent-containing microspheres, the shell 24may comprise a plurality of pores through which the microspheres maypass to subsequently release the therapeutic agent in or near thetargeted tissue; alternatively, the microspheres may release thetherapeutic agent within the shell 24, and then the therapeutic agentmay diffuse through the shell 24 to to the targeted tissue through poresor hydrolocaclly pumped out of the device. The diffusion rate of thetherapeutic agent 26 may be controlled by the thickness of the shell 24,by the number and diameter of the pores within the shell 24, . . . Theconcentration of the therapeutic agent or the medium (gelatin, POE,PLGA, etc.) in which the therapeutic agent is embedded. The barbs 22 maybe made from the same material as the shell 24, and may be disposed inany suitable manner about the outer surface of the shell 24. If theshell 24 is made from a biodegradable material, the type and thicknessof the material used should be sufficient to ensure that all, or nearlyall, of the therapeutic agent 26 has dispersed into the surroundingtissue before the integrity of shell 24 is substantially compromised.

FIG. 3 is a side view of another implant 30. The implant 30 may besolid, as in the implant 10, or shell-like, as in the implant 20. Theimplant 30 has a rod-shaped outer surface 34 from which a therapeuticagent, contained internally of the outer surface 34, diffuses, asdiscussed above. Extending from the outer surface 34 are one or morefirst barbs 32 and one or more second barbs 36. The first barbs 32 pointbackwards along the longitudinal axis 38 to prevent backward movement ofthe implant 30 (i.e., movement opposite to the direction indicated bylongitudinal centerline arrow 38); the second barbs 36 point forwardsalong the longitudinal axis 38 to prevent forward movement of theimplant 30 (i.e., movement along the longitudinal centerline arrow 38).The barbs 32, 36 thus serve as an anchoring system to keep the implant30 at the targeted delivery site; that is, the anchoring systems preventboth forward and backward translational movement of the implant 30.

The barbs 12, 22, 32, 36 in the above examples may be flexible; that is,they may be compressible towards the centerline of the longitudinal axis18, 28, 38. This may assist in the targeted delivery of the implant 10,20, 30. For example, as shown in FIG. 4, an implant 40 may be releasedat a target site by a targeted delivery system 41, which may be acatheter, a syringe, or any other suitable device. As shown, thetargeted delivery system 41 may include a cannula 43 in which theimplant 40 is disposed. The implant 40 has flexible barbs 42 that extentas they exit from the cannula 43.

FIG. 5 is a side view of another embodiment implant 50. The implant 50has a rod-shaped outer surface 54 from which elutes a therapeutic agentcontained therein. Extending from the outer surface 54 is one or moreextensions 52 adapted to prevent both forward and backward translationalmovement of the implant 50, and which thus serve as an anchoring systemto keep the implant 50 at the targeted delivery site. The extensions 52may be flexible, and hence may extend once released from a targeteddelivery device. The extensions 52 point substantially 90 degrees awayfrom the longitudinal axis 58. The anchoring system provided by theextensions 52 may also prevent rotational movement of the implant 50.

Implants of the present invention may be provided radiographic markersthat assist in the imaging of the implants, and hence in the targeteddelivery of the implants. The radiographic markers may be made from anysuitable material, as previously discussed, and may be, for example,ring-shaped, or dispersed as small pellets throughout the implant. Animplant 60 utilizing ring-shaped radiographic markers is depicted inFIG. 6. As shown, one or more radiographically active rings 62 arepositioned in or on the body 64 of the implant 60. Each ring 62 isplaced at a predetermined position within the body 64, and thus whenimaged enables a physician to determine the position and orientation ofthe implant 60. FIG. 7 presents another possible embodiment forradiographic markers as applied to an implant of the present invention.An implant 70 comprises a body portion 74 that holds, and elutes, thetherapeutic agent. Regularly dispersed throughout, or on, the bodyportion 74 are small beads 72 of a radiographically active substance.Imaging of the beads 72 provides a clear indication of the position andorientation of the body portion 74 within the target tissue.Alternatively, the beads 72 may be disposed in or on the body portion 74according to a predetermined pattern; imaging of this pattern presentedby the beads 72 will similarly provide solid reference for the positionand orientation of the body portion 74.

FIG. 8 is a side view of another implant 80. The implant 80 has arod-shaped body portion 84, which may be tapered, from which extends afirst anchoring system 82 and a second anchoring system 86 that securethe implant 80 within the targeted tissue location. The first anchoringsystem 82 is configured as one or more barbs 82, which point backwardswith respect to the forward (or insertion) direction indicated bylongitudinal centerline arrow 88. The barbs 82 thus prevent the implant80 from backing out of the implant site. The barbs 82 may be flexible.The second anchoring system 86 is an end cap 86 that is adapted to abutagainst a tissue plane. A forward surface 89 of the end cap 86 contactsthe tissue plane, and thus prevents forward translational movement, asindicated by centerline arrow 88, of the implant 80. Both the barbs 82and the end cap 86 may be made from the same material as the body potion84. The body portion 84 may be hollow or solid, and may or may not bebiodegradable, as described previously. The body portion 84 contains,and elutes, the desired therapeutic agent. Although the therapeuticagent may be dispersed throughout the body portion 84, as well asthroughout the barbs 82 and end cap 86, it may be desirable to disposethe therapeutic agent only within a forward region of the body portion84. For example, it may be desirable to dispose the therapeutic agentonly within the forward two-thirds of the body portion 84, as indicatedby arrow 81. Alternatively, it may be desirable to have the therapeuticagent in only the forward half of the body portion, as indicated byarrow 83, or only the forward third, as indicated by arrow 85. Indeed,it may be desirable to have the therapeutic agent disposed only within atip region 87 of the body portion 84. Hence, depending upon the region81, 83, 85, 87 selected, the therapeutic agent will only elute from thatspecific region 81, 83, 85, 87 of the implant 80. The forward end 81,83, 85, 87 of the body portion 84 that contains the therapeutic agentmay be termed the active end of the implant 80. The end cap 86 may beformed with the body portion 84, i.e., be monolithic with the bodyportion 84, or may be provided as a separate element. If provided as aseparate element, the end cap 86 and body portion 84 should havecorresponding mating elements that enable a physician to attach the endcap 86 to the body portion 84 after the body portion 84 has beendeployed at a targeted tissue site. Any suitable mating system may beused such as for example, mechanical snap-on or threaded fixation.

As shown in FIG. 9, an implant 90 of the instant invention may bedisposed in a disc 91 to alleviate discogenic pain. A disc 91 to betreated is sandwiched between two vertebrae 93. The implant 90 isinserted into the interior region of the disc 91, such as the annularfibrosus or nucleus pulposus of the disc 91. This embodiment is achievedfor example as shown in FIG. 4, through a hollow cannula. The cannula iswithdraw, deploying the barbs. The implant 90 has an anchoring system 92that extends from the implant 90 to keep the implant 90 firmlyconstrained to the targeted tissue site, preventing forward andbackwards movement of the implant 90 within the disc 91. The implant 90also has an active region 94 that elutes a therapeutic agent 96 into thedisc 91. The concentration gradient of the eluted therapeutic agent 96may extend from 1 cm to as far as 5 cm from the active region 94 of theimplant 90.

The implant 80 of FIG. 8 is shown deployed in the synovial cavity 102 ofa synovial joint 100 in FIG. 10. The joint 100 depicted is an idealizedsynovial joint but roughly approximates the femur-tibia articulation atthe knee. Exemplary placement of the implant 80 is indicated. In thisexample, the placement of the implant 80 is in the joint and is remotefrom the bone. As shown, the forward surface 89 of the end cap 86 abutsagainst the synovial membrane 104, thus preventing forward movement ofthe implant 80 into the joint 100. Similarly, the barbs 82 prevent theimplant 80 from backing out of the joint 100. An active end 106 of theimplant 80 elutes a therapeutic agent 108 into the synovial fluid of thecavity 102.

FIG. 11 is a side view of another implant 110. The implant 110 comprisesa tapered, rod-shaped body portion 114 and a suture 112 that extendsfrom the body 114. The body 114 may be hollow or solid, as previouslydescribed, and made from a biodegradable or non-biodegradable material.The body 114 contains, and elutes, a therapeutic agent. The entire body114 may be active (i.e., elute the therapeutic agent), or instead mayhave an active region in a predetermined position, as indicated earlierfor other embodiments. The suture 112 may be made from a biodegradableor non-biodegradable material. If made from a biodegradable material, itmay be desirable to select a material for the suture 112 that degradessignificantly slower than the body 114. As shown, the suture 112 entersfrom a central region 116 of the body 114, substantially circumnavigatesthe body 114 and then exits from the central region 116. The suture 112,extending from the body portion 114, serves as an anchoring system forthe implant 110. By tying the suture 112 onto adjacent tissue, it ispossible to securely retain the implant 110 at a targeted tissue site,and hence prevent translational movement of the implant 110 within orfrom the targeted tissue site.

FIG. 12 shows an another implant 120 that similarly utilizes a suture122. As in the implant 110, the suture 124 may traverse just under thebody portion 124. In the implant 120, however, the suture 122 enters thebody portion 124 from a first end region 126 of the body 124 and exitsfrom a second end region 128 of the body 124. The end regions 126, 128may include, for example, the outer third of the body portion 124, withrespect to the longitudinal axis 129.

Another embodiment implant 130 is shown in FIG. 13. For the implant 130,the suture 132 enters at or near a first endpoint 136 of the body 134,traverses within the body 134 substantially along the longitudinalcenterline 139, and exits from, or near, a second endpoint 138 of thebody 124. The endpoints 136, 138 are defined by the longitudinalcenterline 139 of the body 134.

It is contemplated that the several drug depot designs 110, 120, 130 maybe used in joint capsules, with the sutures 112, 122, 132 being used toretain the depot 110, 120, 130 up against the inside of the jointcapsule. FIG. 14 shows, for example, deployment of the implant 110 ofFIG. 11 in a synovial joint 140. The bullet-shaped tip of the body 114eases insertion of the implant 110 through the joint capsule tissue 142and minimizes tissue disruption. A very small hole is made in the jointcapsule 142 with a blunt probe, and then the tapered rod 114 is slowlypushed through this hole, slowly stretching the tissues apart tominimize tissue tearing. Once the rod 114 is fully inserted, the hole inthe joint capsule 142 closes upon itself. The suture 112 embedded in therod 114 is left passing through the capsule 142 so that it can be pulledtaught and knotted up against the outside of the joint capsule 142,forcing the depot 110 up against the inside of the joint capsule 142.Having the depot 110 up against the inside of the joint capsule 142 willprevent the depot 110 from interfering with normal joint 140 motion.

FIG. 15 shows the implant 120 of FIG. 12 deployed in a synovial joint150. The suture 122 exits from two points in the joint capsule 152. Theends of the suture 122 may be tied off together or separately. Thisdesign offers the advantage of holding the depot 120 up against theinside of the joint capsule 152 without rotating and potentiallyinterfering with motion of the joint 150.

Several implant designs are contemplated for use in intervetebral discand joint capsules that comprise bead-shaped depots strung togetheralong a suture. Such an embodiment implant 160 is depicted in FIG. 16.Analogous to the embodiments discussed earlier, the beads 164 may be inthe form of a solid, biodegradable material, such as a polymer, loadedwith a therapeutic agent; alternatively, the beads 164 may form a cavitythat is packed with the therapeutic agent, and which may diffuse throughthe walls of the cavity. The beads 164 elute the therapeutic agent whendisposed within the targeted tissue site. The beads 164 may be from XXXXto YYYY in diameter. The suture 162 may be either a degradable or anon-degradable material. Extending from an end of the implant 160 is anoptional needle or barb 166 to serve as an anchoring device that retainsthe strand 160 within the targeted tissue site, such as a disc or jointcapsule.

This implant 160 optimally positions the therapeutic agent eluting beads164 along the route of inflamed tissue, resulting in a more effectivedistribution of the therapeutic agent and clinical effectiveness. Asshown in FIG. 17, the strand 160 may be implanted by inserting a cannula170 containing the strand 160 of beads 164 as far as desired inside, forexample, a disc, joint, or soft tissue, and then deploying the barb 166into the soft tissue (such as the annulus) and slowly retracting thecannula 170, which will result in the implant 160 being pulled from thecannula 170. By fixing, for example, the leading edge of the implant160, the anchoring device 166 retains the beads 164 at the locationwhere the therapeutic agent is desired. FIGS. 18 and 19 illustrate theimplant 160 being deployed in targeted tissue sites. A very small holeis made in an intervertebral disc 180 or in a joint capsule 192 with ablunt probe, through which a cannula is inserted to implant the string160 of beads 164. For example, as shown in FIG. 18, the implant 160 maybe deployed inside a disc 180, with the anchoring device 166 embeddedwithin the annular fibrosus of the disc 180. The beads 164 may extendinside the disc 180, and then externally along the nerve root 182. Asshown in FIG. 19, the implant 160 may be deployed transverse across ajoint 190, resulting in a more uniform distribution of the therapeuticagent within the synovial cavity 194 of the joint 190. The suture 162 atthe ends of the implant 160 may be tied off to the joint capsule 192 toanchor the implant 160 within the joint 190.

The present invention provides another method for administering atherapeutic agent to a targeted tissue site. As shown in FIG. 20, thetargeted tissue site may be a spinal canal 200 or tissue surrounding thespinal canal 200, such as a disc 202 or a nerve root 204. The spinalcord 206 runs through the spinal canal 200, which is provided by thevertebrae 208. As discussed earlier, microspheres 209 encapsulating thedesired therapeutic agent may be formed in a known manner. Thesemicrospheres 209 may then be deployed into the spinal canal 200, such asby injecting a carrier containing the microspheres 209 into the spinalcanal 200. The microspheres 209 then elute the therapeutic agent intothe spinal canal 200. The microspheres 209 may disperse to thesurrounding tissue, such as the nerve root 204 or the disc 202.Alternatively, to provide therapeutic treatment primarily to the disc202 alone, the therapeutic-containing microspheres 209 may be directlyinjected into the disc 202. As shown in FIG. 21, microspheres 219 loadedwith a therapeutic agent may be injected into a synovial cavity 212 totreat a joint 210. A syringe or similar device may be used to deploy themicrospheres 219 into the joint cavity 212.

Microspheres, much like a fluid, may disperse relatively quickly,depending upon the surrounding tissue type, and hence disperse thetherapeutic agent. In some situations, this may be desirable; in others,it may be more desirable to keep the therapeutic agent tightlyconstrained to a well-defined target site. The present inventioncontemplates the use of adherent gels to so constrain dispersal of thetherapeutic agent. These gels may be deployed, for example, in a discspace, in a spinal canal, or in surrounding tissue, or in a joint space,such as a synovial cavity in this embodiment the gel is an adherentand/or settable gel in order to stay in place within a joint space.

In one embodiment, a depot comprises an adherent gel comprising atherapeutic agent that is evenly distributed throughout the gel. The gelmay be of any suitable type, as previously indicated, and should besufficiently viscous as to prevent the gel from migrating from thetargeted delivery site once deployed; the gel should, in effect, “stick”to the targeted tissue site. The gel may, for example, solidify uponcontact with the targeted tissue, or after deployment from a targeteddelivery system. The targeted delivery system may be, for example, asyringe, a catheter or any other suitable device. The targeted deliverysystem may inject or spray the gel into or on the targeted tissue site.The therapeutic agent may be mixed into the gel prior to the gel beingdeployed at the targeted tissue site. The gel may be biodegradable. Forthe non-settable gels, they may be sold premixed and just delivered, butfor the adherent and/or settable gel, they may need to be two componentdelivery systems that mix the two components upon injection to activatea chemical process to cause them to stick or set up.

FIG. 22 illustrates a gel 212, imbued with a therapeutic agent, deployedaround a targeted tissue site, a nerve root 210. The gel 212, eitherviscous or solid once deployed, keeps the therapeutic agent closelybound to the nerve root 210, thereby providing a therapeuticallyeffective dosage of the therapeutic agent to the nerve root 210, withthe dosage gradient rapidly falling off outside of the region of the gel212. The therapeutic agent is therefore tightly targeted at the nerveroot 210.

Alternatively, rather than directly admixing the therapeutic agent intothe gel, the present invention also contemplates instead dispersingmicrospheres within the gel, the microspheres loaded with thetherapeutic agent. In one embodiment, the microspheres provide for asustained release of the therapeutic agent. In yet another embodiment,the gel, which is biodegradable, prevents the microspheres fromreleasing the therapeutic agent; the microspheres thus do not releasethe therapeutic agent until they have been released from the gel. Thisembodiment is depicted in FIG. 23, which shows a gel 222 deployed arounda nerve root 220, the targeted tissue site. Dispersed within the gel 222are a plurality of microspheres 226 that encapsulate the desiredtherapeutic agent. Dashed line 227 indicates the original deploymentregion of the gel 222; solid line 225 indicates the current deploymentregion of the gel 222 due to degradation of the gel 222. Microspheres226 are thus released from the gel 222. Certain of these microspheres228 degrade once released from the gel 222, thus releasing thetherapeutic agent.

It will be appreciated that a localized delivery device, such as a pumpor the like, may be used to deliver the microspheres to the targetedtissue site. Similarly, a pump may be used to deliver the presentinvention gel, either with or without microspheres, to the target site.Examples of localized delivery systems are presented in co-pending U.S.patent application Ser. No. 11/091,348, which is incorporated herein byreference.

The use of depot implants to deliver anti-inflammatory or anaboliccompounds to intervertebral discs or articulating joints has not beenpreviously disclosed. The specific designs disclosed and contemplated inthis invention provide a way to insert depot implants into discs orjoint capsules with minimal tissue disruption and interfering withnormal joint motion. It also prevents the depots from migrating awayfrom the inflamed tissue and allowing for more uniform distribution ofthe drug.

All publications cited in the specification, both patent publicationsand non-patent publications, are indicative of the level of skill ofthose skilled in the art to which this invention pertains. All thesepublications are herein fully incorporated by reference to the sameextent as if each individual publication were specifically andindividually indicated as being incorporated by reference.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the following claims.

1. A drug depot implant comprising: a body; a therapeutic agent disposedin the body; and an anchoring system extending from the body, theanchoring system adapted to limit movement of the body from a targetedtissue; wherein the body is capable of eluting the therapeutic agent. 2.The drug depot implant of claim 1 wherein the body is rod-shaped, andthe anchoring system extends from the rod-shaped body and is adapted tolimit translational movement of the body along a longitudinal axis ofthe rod-shaped body.
 3. The drug depot implant of claim 2 wherein theanchoring system is a barb.
 4. The drug depot implant of claim 3 whereinthe barb is flexible.
 5. The drug depot implant of claim 2 wherein theanchoring system provides a surface adapted to abut against a tissueplane.
 6. The drug depot implant of claim 5 wherein the anchoring systemis an end cap disposed on an end of the rod-shaped body.
 7. The drugdepot implant of claim 2 wherein the anchoring system is a suture. 8.The drug depot implant of claim 1 further comprising a radiographicmarker adapted to assist in radiographic imaging of the drug depotimplant.
 9. The drug depot implant of claim 8 wherein the radiographicmarker is selected from the group consisting of barium, calciumphosphate and metal beads.
 10. The drug depot implant of claim 1 whereinthe body comprises an active region within the body, the therapeuticagent disposed exlusively within the active region.
 11. The drug depotimplant of claim 1 wherein the body is formed from a solid,biodegradable material, and the therapeutic agent is dispersed in atleast a portion of the biodegradable material.
 12. The drug depotimplant of claim 11 further comprising a plurality of microspheresdisposed in the biodegradable material, the microspheres encapsulatingat least a portion of the therapeutic agent.
 13. The drug depot implantof claim 1 wherein the body comprises a shell that defines a cavity, thetherapeutic agent disposed in the cavity, the shell at least partlypermeable to the therapeutic agent.
 14. The drug depot implant of claim13 further comprising a plurality of microspheres disposed in thecavity, the microspheres encapsulating at least a portion of thetherapeutic agent.
 15. The drug depot implant of claim 13 wherein theshell is biodegradable.
 16. The drug depot implant of claim 1 whereinthe targeted tissue site is a synovial joint.
 17. The drug depot implantof claim 1 wherein the targeted tissue site is a soft tissue.
 18. Thedrug depot implant of claim 17 wherein the soft tissue is selected fromthe group consisting of muscle, ligament, tendon, and cartilage.
 19. Thedrug depot implant of claim 1 wherein the targeted tissue site is adisc.
 20. The drug depot implant of claim 1 wherein the drug depotimplant provides an optimal concentration of the therapeutic agent from1 cm to 5 cm from the drug depot implant.
 21. The drug depot implant ofclaim 1 wherein the therapeutic agent is an anti-inflammatory agent. 22.The drug depot implant of claim 21 wherein the anti-inflammatory agentis specific for a target selected from the group consisting of TNF,IL-1, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, GM-CSF, M-CSF, MCP-1,MIP-1, RANTES, ENA-78, OSM, FGF, PDGF, VEGF, steroids, nonsteroidals,and NFkb inhibitors.
 23. The drug depot implant of claim 22 wherein theanti-inflammatory agent is specific for TNF.
 24. The drug depot implantof claim 23 wherein the anti-inflammatory agent is selected from thegroup consisting of soluble tumor necrosis factor α receptors, pegylatedsoluble tumor necrosis factor α receptors, monoclonal antibodies,polyclonal antibodies, antibody fragments, COX-2 inhibitors,metalloprotease inhibitors, such as TAPI, glutamate antagonists, glialcell derived neurotrophic factors (GDNF), B2 receptor antagonists,Substance P receptor (NK1) antagonists, Downstream regulatory elementantagonistic modulator (DREAM), iNOS, inhibitors of tetrodotoxin(TTX)-resistant Na+-channel receptor subtypes PN3 and SNS2, inhibitorsof interleukins, such as IL-1, IL-6, IL-8 and IL-10, TNF bindingprotein, dominant-negative TNF variants, Nanobodies™, kinase inhibitors,Adalimumab, Infliximab, Etanercept, Pegsunercept (PEG sTNF-R1),Onercept, Kineret®, sTNF-R1, CDP-870, CDP-571, CNI-1493, RDP58, ISIS104838, 1>3-β-D-glucans, Lenercept, PEG-sTNFRII Fc Mutein, D2E7,Afelimomab, AMG 108, 6-methoxy-2-napthylacetic acid) or betamethasone,capsaiein, civanide, TNFRc, ISIS2302 and GI 129471, integrinantagonists, alpha-4 beta-7 integrin antagonists, cell adhesioninhibitors, interferon gamma antagonists, CTLA4-Ig agonists/antagonists(BMS-188667), CD40 ligand antagonists, Humanized anti-IL-6 mAb (MRA,Tocilizumab, Chugai), HMGB-1 mAb (Critical Therapeutics Inc.), anti-IL2Rantibody (daclizumab, basilicimab), ABX (anti IL-8 antibody),recombinant human IL-10, HuMax IL-15 (anti-IL 15 antibody), NF Kappa Binhibitors, glucocorticoids, clonidine, nonsteroidal anti-inflammatorydrugs (NSAIDS), sulindac and tepoxalin, antioxidants, dithiocarbamate,sulfasalazine [2-hydroxy-5-[-4-[C2-pyridinylamino)sulfonyl]azo]benzoicacid] and flucinolone and combinations thereof.
 25. The drug depotimplant of claim 1 wherein the therapeutic agent is a osteoinductivegrowth factor.
 26. The drug depot implant of claim 25 wherein theosteoinductive growth factor is selected from the group consisting ofBMP-1, BMP-2, rhBMP-2, BMP-3, BMP-4, rhBMP-4, BMP-5, BMP-6, rhBMP-6,BMP-7[OP-1], rhBMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13,BMP-14, BMP-15, BMP-16, BMP-17, BMP-18, GDF-5, LIM mineralizationprotein, platelet derived growth factor (PDGF), transforming growthfactor β (TGF-β), insulin-related growth factor-I (IGF-I),insulin-related growth factor-II (IGF-II), fibroblast growth factor(FGF), beta-2-microglobulin (BDGF II), and rhGDF-5.
 27. The drug depotimplant of claim 26 wherein the osteoinductive growth factor is BMP-2.28. The drug depot implant of claim 1 wherein the therapeutic agent is akinase inhibitor.
 29. The drug depot implant of claim 28 wherein thekinase inhibitor is selected from the group consisting of Gleevec,Herceptin, Iressa, imatinib (STI571), herbimycin A, tyrphostin 47,erbstatin, genistein, staurosporine, PD98059, SB203580, CNI-1493,VX-50/702, SB203580, BIRB 796, Glaxo P38 MAP Kinase inhibitor, RWJ67657,UO126, Gd, SCIO-469, RO3201195, and Semipimod.
 30. The drug depotimplant of claim 1 wherein the therapeutic agent is ISIS2302 or GI129471.
 31. A method for delivering a therapeutic agent to a targetedtissue site, the method comprising injecting into the targeted tissuesite a plurality of microspheres encapsulating the therapeutic agent.32. The method of claim 31 wherein the targeted tissue site is asynovial joint.
 33. The method of claim 31 wherein the targeted tissuesite is a disc space.
 34. The method of claim 31 wherein the targetedtissue site is spinal canal.
 35. The method of claim 31 wherein thetargeted tissue site is soft tissue surrounding a spinal canal.
 36. Themethod of claim 31 wherein the therapeutic agent is an anti-inflammatoryagent.
 37. The method of claim 36 wherein the anti-inflammatory agent isspecific for a target selected from the group consisting of TNF, IL-1,IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, GM-CSF, M-CSF, MCP-1, MIP-1,RANTES, ENA-78, OSM, FGF, PDGF, and VEGF.
 38. The method of claim 31wherein the therapeutic agent is an osteoinductive growth factor. 39.The method of claim 38 wherein the osteoinductive growth factor isselected from the group consisting of BMP-1, BMP-2, rhBMP-2, BMP-3,BMP-4, rhBMP-4, BMP-5, BMP-6, rhBMP-6, BMP-7[OP-1], rhBMP-7, BMP-8,BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17,BMP-18, GDF-5, LIM mineralization protein, platelet derived growthfactor (PDGF), transforming growth factor β (TGF-β), insulin-relatedgrowth factor-I (IGF-I), insulin-related growth factor-II (IGF-II),fibroblast growth factor (FGF), beta-2-microglobulin (BDGF II), andrhGDF-5.
 40. The method of claim 31 wherein the therapeutic agent is akinase inhibitor.
 41. The method of claim 40 wherein the kinaseinhibitor is selected from the group consisting of Gleevec, Herceptin,Iressa, imatinib (STI571), herbimycin A, tyrphostin 47, erbstatin,genistein, staurosporine, PD98059, SB203580, CNI-1493, VX-50/702,SB203580, BIRB 796, Glaxo P38 MAP Kinase inhibitor, RWJ67657, UO126, Gd,SCIO-469, RO3201195, and Semipimod.
 42. The method of claim 31 whereinthe therapeutic agent is ISIS2302 or GI
 129471. 43. A method fordelivering a therapeutic agent to a targeted tissue site, the methodcomprising injecting into the targeted tissue site a gel or solutioncomprising the therapeutic agent, the gel capable of adhering to thetargeted tissue site.
 44. The method of claim 43 wherein the gel orsolution hardens after contacting the targeted tissue site.
 45. Themethod of claim 43 wherein the gel further comprises a plurality ofmicrospheres, the microspheres encapsulating at least a portion of thetherapeutic agent.
 46. The method of claim 43 wherein the targetedtissue site is a synovial joint.
 47. The method of claim 43 wherein thetargeted tissue site is a disc space.
 48. The method of claim 43 whereinthe targeted tissue site is spinal canal.
 49. The method of claim 43wherein the targeted tissue site is soft tissue surrounding a spinalcanal.
 50. The method of claim 43 wherein the therapeutic agent is ananti-inflammatory agent.
 51. The method of claim 50 wherein theanti-inflammatory agent is specific for a target selected from the groupconsisting of TNF, IL-1, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, GM-CSF,M-CSF, MCP-1, MIP-1, RANTES, ENA-78, OSM, FGF, PDGF, and VEGF.
 52. Themethod of claim 43 wherein the therapeutic agent is an osteoinductivegrowth factor.
 53. The method of claim 52 wherein the osteoinductivegrowth factor is selected from the group consisting of BMP-1, BMP-2,rhBMP-2, BMP-3, BMP-4, rhBMP-4, BMP-5, BMP-6, rhBMP-6, BMP-7[OP-1],rhBMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15,BMP-16, BMP-17, BMP-18, GDF-5, LIM mineralization protein, plateletderived growth factor (PDGF), transforming growth factor β (TGF-β),insulin-related growth factor-I (IGF-I), insulin-related growthfactor-II (IGF-II), fibroblast growth factor (FGF), beta-2-microglobulin(BDGF II), and rhGDF-5.
 54. The method of claim 43 wherein thetherapeutic agent is a kinase inhibitor.
 55. The method of claim 54wherein the kinase inhibitor is selected from the group consisting ofGleevec, Herceptin, Iressa, imatinib (STI571), herbimycin A, tyrphostin47, erbstatin, genistein, staurosporine, PD98059, SB203580, CNI-1493,VX-50/702, SB203580, BIRB 796, Glaxo P38 MAP Kinase inhibitor, RWJ67657,UO126, Gd, SCIO-469, RO3201195, and Semipimod.
 56. The method of claim43 wherein the therapeutic agent is ISIS2302 or GI
 129471. 57. A drugdepot implant comprising a plurality of beads connected together bysuture, the beads comprising a therapeutic agent.
 58. The drug depotimplant of claim 57 wherein the beads are each formed from a solid,biodegradable material, and the therapeutic agent is dispersedthroughout the biodegradable material.
 59. The drug depot implant ofclaim 57 wherein each bead comprises a shell that defines a cavity, thetherapeutic agent is disposed within the cavity, the shell at leastpartly permeable to the therapeutic agent.
 60. The drug depot implant ofclaim of claim 59 wherein the shell is biodegradable.
 61. The drug depotimplant of claim 57 wherein an anchoring system is connected to thesuture.
 62. The drug depot implant of claim 57 wherein an anchoringsystem is the leading bead.
 63. The drug depot implant of claim 61wherein the anchoring system is a hook or a barb.
 64. The drug depotimplant of claim 61 wherein the beads are linearly disposed along thesuture, and the anchoring system is attached to a leading end of thesuture.
 65. The drug depot implant of claim 61 wherein an anchoringsystem is the leading bead.
 66. The drug depot implant of claim 57wherein the therapeutic agent is an anti-inflammatory agent.
 67. Thedrug depot implant of claim 66 wherein the anti-inflammatory agent isspecific for a target selected from the group consisting of TNF, IL-1,IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, GM-CSF, M-CSF, MCP-1, MIP-1,RANTES, ENA-78, OSM, FGF, PDGF, and VEGF.
 68. The drug depot implant ofclaim 66 wherein the anti-inflammatory agent is specific for TNF. 69.The drug depot implant of claim 68 wherein the anti-inflammatory agentis selected from the group consisting of soluble tumor necrosis factor αreceptors, pegylated soluble tumor necrosis factor α receptors,monoclonal antibodies, polyclonal antibodies, antibody fragments, COX-2inhibitors, metalloprotease inhibitors, such as TAPI, glutamateantagonists, glial cell derived neurotrophic factors (GDNF), B2 receptorantagonists, Substance P receptor (NK1) antagonists, Downstreamregulatory element antagonistic modulator (DREAM), iNOS, inhibitors oftetrodotoxin (TTX)-resistant Na+-channel receptor subtypes PN3 and SNS2,inhibitors of interleukins, such as IL-1, IL-6, IL-8 and IL-10, TNFbinding protein, dominant-negative TNF variants, Nanobodies™, kinaseinhibitors, Adalimumab, Infliximab, Etanercept, Pegsunercept (PEGsTNF-R1), Onercept, Kineret®, sTNF-R1, CDP-870, CDP-571, CNI-1493,RDP58, ISIS 104838, 1>3-β-D-glucans, Lenercept, PEG-sTNFRII Fc Mutein,D2E7, Afelimomab, AMG 108, 6-methoxy-2-napthylacetic acid) orbetamethasone, capsaiein, civanide, TNFRc, ISIS2302 and GI 129471,integrin antagonists, alpha-4 beta-7 integrin antagonists, cell adhesioninhibitors, interferon gamma antagonists, CTLA4-Ig agonists/antagonists(BMS-188667), CD40 ligand antagonists, Humanized anti-IL-6 mAb (MRA,Tocilizumab, Chugai), HMGB-1 mAb (Critical Therapeutics Inc.), anti-IL2Rantibody (daclizumab, basilicimab), ABX (anti IL-8 antibody),recombinant human IL-10, HuMax IL-15 (anti-IL 15 antibody), NF Kappa Binhibitors, glucocorticoids, clonidine, nonsteroidal anti-inflammatorydrugs (NSAIDs), sulindac and tepoxalin, antioxidants, dithiocarbamate,sulfasalazine [2-hydroxy-5-[-4-[C2-pyridinylamino)sulfonyl]azo]benzoicacid] and flucinolone and combinations thereof.
 70. The drug depotimplant of claim 57 wherein the therapeutic agent is a osteoinductivegrowth factor.
 71. The drug depot implant of claim 70 wherein theosteoinductive growth factor is selected from the group consisting ofBMP-1, BMP-2, rhBMP-2, BMP-3, BMP-4, rhBMP-4, BMP-5, BMP-6, rhBMP-6,BMP-7[OP-1], rhBMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13,BMP-14, BMP-15, BMP-16, BMP-17, BMP-18, GDF-5, LIM mineralizationprotein, platelet derived growth factor (PDGF), transforming growthfactor β (TGF-β), insulin-related growth factor-I (IGF-I),insulin-related growth factor-II (IGF-II), fibroblast growth factor(FGF), beta-2-microglobulin (BDGF II), and rhGDF-5.
 72. The drug depotimplant of claim 70 wherein the osteoinductive growth factor is BMP-2.73. The drug depot implant of claim 57 wherein the therapeutic agent isa kinase inhibitor.
 74. The drug depot implant of claim 73 wherein thekinase inhibitor is selected from the group consisting of Gleevec,Herceptin, Iressa, imatinib (STI571), herbimycin A, tyrphostin 47,erbstatin, genistein, staurosporine, PD98059, SB203580, CNI-1493,VX-50/702, SB203580, BIRB 796, Glaxo P38 MAP Kinase inhibitor, RWJ67657,UO126, Gd, SCIO-469, RO3201195, and Semipimod.
 75. The drug depotimplant of claim 57 wherein the therapeutic agent is ISIS2302 or GI129471.